Aminediol protease inhibitors

ABSTRACT

Novel aminediol compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds in inhibiting retroviral protease, particularly useful in the treatment and/or prevention of HIV infection (AIDS).

This is a continuation-in-part of U.S. patent application Ser. No.07/927,027, filed Aug. 6, 1992 by Gordon et al., now abandoned, which isa continuation-in-part of U.S. patent application Ser. No. 07/916,916,filed Jul. 20, 1992 by Gordon et al., now abandoned; wherein both of theaforementioned patent applications are incorporated by reference hereinin their entirety.

FIELD OF THE INVENTION

The present invention relates to novel aminediol compounds, topharmaceutical compositions containing these compounds, and to methodsof using these compounds in inhibiting the replication of retroviruses.The present invention particularly relates to novel aminediol compoundsuseful in the treatment and/or prevention of Acquired ImmunodeficiencySyndrome (AIDS).

SUMMARY OF THE INVENTION

The present invention provides compounds of the following formula I:##STR1## where A^(a), A^(b) and A^(c) are independently:

(1) hydrogen;

(2) alkyl, especially lower alkyl; ##STR2## D^(a) and D^(b) areindependently selected from groups of the formula: ##STR3## where D^(a)and D^(b) are bonded to the groups A^(a) and A^(b), respectively,through the moiety --E--N(R⁸)--, where E is a single bond or a peptidechain containing 1 to 4 amino acids, the N-terminus of which is bondedto A^(a) when E is part of D^(a) or to A^(b) when E is part of D^(b) ;

R¹ and R² are independently:

(1) hydrogen;

(2) alkyl, especially lower alkyl;

(3) alkenyl, especially lower alkenyl;

(4) aryl;

(5) heterocyclo; or

(6) carbocyclo, such as cycloalkyl;

R³ and R⁴ are independently:

(a) hydrogen;

(b) alkyl, especially lower alkyl;

(c) aryl;

(d) heterocyclo;

(e) carbocyclo, such as cycloalkyl;

(f) when R³ and R⁴ are bonded to a common nitrogen atom, R³ and R⁴ maybe joined, together with that nitrogen atom, to form a heterocyclic ringsystem, such as a 5 to 7 membered heterocyclic ring; or

(g) when E is a single bond and R³ is part of A^(a) or A^(b), R³ may,together with R⁸, form an alkylene group, for example, having one tofive carbons, such as wherein R³ and R⁸, together with the atoms towhich they are bonded, form the cyclic moiety: ##STR4## R⁵, R⁶ and R⁷are independently: (a) hydrogen;

(b) alkyl, especially lower alkyl;

(c) aryl;

(d) carbocyclo, such as cycloalkyl;

(e) fluorenyl;

(f) heterocyclo;

(g) R⁵, R⁶ and R⁷ may, independently, be joined, together with thecarbon atom to which they are bonded, to form a mono-, bi- or tricycliccarbocyclic ring system, especially wherein each ring contains 3 to 7carbon atoms, or a mono-, bi- or tricyclic heterocyclic ring system;

(h) alkynyl;

(i) alkenyl; or

(j) when E is a single bond and R⁵, R⁶ and R⁷ are part of A^(a) orA^(b), one of R⁵, R⁶, or R⁷ may, together with R⁸, form an alkylenegroup, for example, having one to three carbons, such as wherein R⁵ andR⁶ are methyl and R⁷ and R⁸, together with the atoms to which they arebonded, form the cyclic moiety: ##STR5## R⁸ is: (a) hydrogen;

(b) alkyl, especially unsubstituted lower alkyl or aryl-lower alkyl;

(c) R⁸ and R⁹ may be joined, together with the atoms to which they arebonded, to form a heterocyclic ring system, for example, a 5 to 7membered monocyclic heterocyclic ring;

(d) R⁸ may be joined together with R⁵, R⁶ or R⁷ as described above;

(e) R⁸ may be joined together with R³ as described above; or

(f) R⁸ and R¹¹ may be joined, together with the atoms to which they arebonded, to form a heterocyclic ring system, such as where R⁸ and R¹¹together are an alkylene group;

R⁹ and R^(9') are independently:

(a) hydrogen;

(b) alkyl, especially lower alkyl;

(c) alkenyl, especially lower alkenyl;

(d) alkynyl;

(e) aryl;

(f) heterocyclo;

(g) carbocyclo, such as cycloalkyl;

(h) R⁹ may be joined together with R⁸ as described above; or

(i) R⁹ and R^(9') may be joined, together with the carbon atom to whichthey are bonded, to form a carbocyclic group, such as 5- or 6-memberedcarbocyclic ring;

R¹⁰ is:

(a) hydrogen;

(b) alkyl, such as unsubstituted lower alkyl or hydroxy-lower alkyl,cycloalkyl-lower alkyl, aryl-lower alkyl or heterocyclo-lower alkyl;

(c) alkenyl, especially lower alkenyl;

(d) alkynyl;

(e) carbocyclo, such as cycloalkyl;

(f) aryl; or

(g) R¹⁰ and R¹¹ taken together may form a a bond to give a keto (C═O)group;

R¹¹ is:

(a) hydrogen;

(b) a hydroxyl protecting group, such as alkyl;

(c) R¹¹ may be joined together with R⁸ as described above; or

(d) R¹¹ may, together with R¹⁰, form a bond to give a keto group asdescribed above;

Z is oxygen or sulfur; and

p and q are, independently, integers from 0 to 4; and

salts, preferably pharmaceutically acceptable salts, thereof.

The compounds of the present invention inhibit the replication ofretroviruses. The present invention thus also provides methods, andpharmaceutical compositions, for the treatment and/or prevention ofdiseases caused by such pathogenic organisms.

DETAILED DESCRIPTION OF THE INVENTION

The terms "alk" or "alkyl", as employed herein alone or as part ofanother group, denote both straight and branched chain, optionallysubstituted saturated radicals, for example, containing 1 to 12 carbons,most preferably 1 to 8 carbons, in the normal chain. It is understood,therefore, that throughout this specification the terms "alk" and"alkyl" denote both unsubstituted groups such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, n-hexyl andthe like, as well as substituted groups such as phenylmethyl and thelike. Exemplary substituents may include one or more, such as 1, 2 or 3,of the following:

(1) hydroxy (or protected hydroxy);

(2) oxo (i.e. ═o), with the proviso that the carbon bearing the oxogroup is not adjacent to a heteroatom;

(3) carboxy;

(4) halo (especially to form trihaloalkyl, particularlytrifluoromethyl);

(5) alkoxy, such as phenyl-lower alkoxy or

    R.sup.16 --[O--(CH.sub.2).sub.m ].sub.n --O--

where m is an integer from 2 to 5; n is an integer from 1 to 5; and R¹⁶is:

(a) hydrogen;

(b) alkyl, especially unsubstituted lower alkyl or alkoxy-lower alkyl;

(c) aryl; or

(d) heterocyclo;

(6) aryloxy;

(7) alkoxycarbonyl; ##STR6##

where R¹² and R¹³ are independently:

(a) hydrogen;

(b) alkyl, especially lower alkyl;

(c) aryl;

(d) heterocyclo;

(e) carbocyclo, such as cycloalkyl;

(f) R¹² and R¹³ may be joined, together with the nitrogen atom to whichthey are bonded, to form a 5 to 7 membered heterocyclic ring;

(9) (R¹²) (R¹³) N--, such as amino (H₂ N--); ##STR7##

where R¹⁴ is:

(a) hydrogen;

(b) alkyl, especially lower alkyl;

(c) aryl;

(d) heterocyclo;

(e) carbocyclo, such as cycloalkyl; or

(f) R¹⁴ and R¹⁵ may be joined to form an alkylene group of three to fivecarbon atoms; and

R¹⁵ is:

(a) hydrogen;

(b) alkyl, especially lower alkyl;

(c) alkenyl, especially lower alkenyl;

(d) aryl;

(e) heterocyclo;

(f) carbocyclo, such as cycloalkyl; ##STR8## wherein R⁵, R⁶ and R⁷ are,independently, those groups (a) through (i) recited for R⁵, R⁶ and R⁷above; or

(h) R¹⁵ may be joined together with R¹⁴ as described above; ##STR9##

(12) carbocyclo, such as cycloalkyl;

(13) heterocyclo;

(14) heterocyclooxy;

(15) aryl;

(16) alkylcarbonyloxy, such as lower alkylcarbonyloxy;

(17) arylcarbonyloxy;

(18) cyano;

(19) mercapto;

(20) alkenyl;

(21) alkynyl, such as ethynyl (e.g., forming a propargyl group);

(22) alkylthio;

(23) arylthio;

(24) trialkylsilyl, such as trimethylsilyl;

(25) azo (i.e., R¹⁶ O--N═ where R¹⁶ is as defined above, preferablyhydrogen (to form an oxime group (HO--N═)) or unsubstituted alkyl (toform an unsubstituted alkoxyimino group (alkyl--O--N═)); or

(26) (R¹²)(R¹³)N--C(O)--O--, where R¹² and R¹³ are as defined above.

The term "alkoxy" denotes an alkyl group bonded through an oxygen bridge(--O--); the term "alkylthio" denotes an alkyl group bonded through asulfur bridge (--S--); the term "alkoxycarbonyl" (also referred to as"carboalkoxy") denotes an alkoxy group attached to a carbonyl group toform an ester; the term "alkylcarbonyloxy" denotes an alkyl group bondedto a carbonyl group which is in turn bonded through an oxygen bridge;the term "aminocarbonyloxy" denotes an amino group bonded through acarbonyl group which is, in turn, bonded through an oxygen bridge; theterm "alkylaminocarbonyloxy" denotes an alkyl group bonded through anaminocarbonyloxy group as described above; the term "alkylaminocarbonyl"denotes an alkyl group bonded through an amino group which is, in turn,bonded through a carbonyl group; and the term "alkylene" denotes adivalent alkyl group. With respect to exemplary alkyl groups which aresubstituted, the term "alkoxy-alkyl" specifically denotes an alkoxygroup bonded through an alkyl group; the term "aryl-alkyl" specificallydenotes an aryl group bonded through an alkyl group; the term"heterocyclo-alkyl" specifically denotes a heterocyclo group bondedthrough an alkyl group; the term "cycloalkyl-alkyl" specifically denotesa cycloalkyl group bonded through an alkyl group; and the term"hydroxy-alkyl" specifically denotes one or more hydroxyl groupsattached to an alkyl group. In each of the aforementioned terms, "alkyl"may be further substituted, or unsubstituted, as defined above.Likewise, "fluorenylalkyl" specifically denotes a fluorenyl group bondedthrough alkyl. Similarly, the terms "arylalkoxy", "alkoxyalkoxy","hydroxyalkoxy", "heterocycloalkoxy", "aminoalkoxy","aminocarbonyloxyalkoxy", "heterocyclocarbonylalkoxy","heterocyclooxyalkoxy", alkoxycarbonylalkoxy" and "carboxyalkoxy"specifically denote alkoxy substituted by aryl, alkoxy, hydroxy,heterocyclo, amino, aminocarbonyloxy, heterocyclocarbonyl,heterocyclooxy, alkoxycarbonyl and carboxy, respectively.

The term "lower alkyl", as employed herein alone or as part of anothergroup, denotes optionally substituted groups as described above foralkyl containing 1 to 6 carbon atoms in the normal chain. Lower alkylgroups are preferred alkyl groups.

The term "alkenyl", as employed herein alone or as part of anothergroup, denotes both straight and branched chain, optionally substitutedradicals, for example, containing 2 to 12 carbons in the normal chain,most preferably 2 to 8 carbons, which contain at least one carbon tocarbon double bond and which are directly attached through one of thecarbons composing the double bond. It is understood, therefore, thatthroughout this specification, the term "alkenyl" denotes bothunsubstituted groups such as ethenyl, propenyl, butenyl, pentenyl,hexenyl, and the like, as well as substituted groups. Exemplarysubstituents may include one or more, such as 1, 2 or 3, of thefollowing:

(1) alkyl, especially lower alkyl;

(2) aryl;

(3) carbocyclo, such as cycloalkyl;

(4) heterocyclo;

(5) carboxy;

(6) halo; ##STR10##

(8) cyano;

(9) alkoxycarbonyl;

(10) trialkylsilyl; or

(11) alkynyl.

The term "lower alkenyl", as employed herein alone or as part of anothergroup, denotes optionally substituted groups as described above foralkenyl containing 2 to 6 carbon atoms in the normal chain. Loweralkenyl groups are preferred alkenyl groups.

The term "alkynyl", as employed herein alone or as part of anothergroup, denotes both straight and branched chain, optionally substitutedradicals, for example, containing 2 to 12 carbons in the normal chain,most preferably 2 to 8 carbons, which contain at least one carbon tocarbon triple bond and which are directly attached through one of thecarbons composing the triple bond. It is understood, therefore, thatthroughout this specification, the term "alkynyl" denotes bothunsubstituted groups such as ethynyl, methyl-ethynyl, and the like, aswell as substituted groups. Exemplary substituents may include one ormore, such as 1, 2 or 3, of the following:

(1) alkyl, especially lower alkyl;

(2) aryl;

(3) carbocyclo, such as cycloalkyl;

(4) heterocyclo;

(5) carboxy; ##STR11##

(7) cyano;

(8) alkoxycarbonyl;

(9) alkenyl; or

(10) trialkylsilyl.

The terms "carbocyclo", "carbocyclic" or "carbocyclic ring system", asemployed herein alone or as part of another group, denote an optionallysubstituted, saturated or partially unsaturated, homocyclic carbon ringsystem, such as a cycloalkenyl ring system, which is partiallyunsaturated, or most preferably, a cycloalkyl ring system, which isfully saturated, wherein the aforementioned cycloalkenyl and cycloalkylring systems are, according to the above definition, optionallysubstituted. Such cyclic groups preferably contain from 1 to 3 rings andfrom 3 to 12, most preferably from 3 to 7, carbons per homocyclic ring.It is understood, therefore, that throughout this specification theterms "carbocyclo", "carbocyclic" and "carbocyclic ring system" denoteboth unsubstituted groups exemplified by monocyclic groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;bicyclic groups such as octahydropentalenyl, decalin, norbornyl,spirocycloheptyl (e.g., spiro[2.4]heptyl), spirocyclooctyl (e.g.,spiro[3.4]octyl), spirocyclononyl (e.g. spiro[4.4]nonyl), and the like;and tricyclic groups such as adamantyl, as well as substituted groups.Exemplary substituents may include one or more, such as 1, 2 or 3, ofthe following:

(1) alkyl, especially lower alkyl;

(2) hydroxy (or protected hydroxy);

(3) halo;

(4) mercapto;

(5) cyano;

(6) carboxy;

(7) alkoxycarbonyl; ##STR12##

(9) alkylcarbonyloxy, such as lower alkylcarbonyloxy;

(10) arylcarbonyloxy;

(11) (R¹²) (R¹³)N--, such as amino (H₂ N--);

(12) alkoxy;

(13) aryl, such as where said aryl group is bonded through a single bondor is fused to said carbocyclo group (e.g. to form a tetrahydronaphthyl,indanyl or indenyl group), and wherein, in each case, thearyl-carbocyclo moiety so formed is bonded through the carbocyclo group;

(14) heterocyclo;

(15) heterocyclooxy;

(16) oxo (═O);

(17) aryloxy;

(18) alkylthio;

(19) arylthio; ##STR13##

(21) alkenyl;

(22) alkynyl; or

(23) trialkylsilyl.

The terms "ar" or "aryl", as employed herein alone or as part of anothergroup, denote homocyclic, optionally substituted aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl,biphenyl and the like. It is understood, therefore, that throughout thisspecification, the terms "ar" and "aryl" denote unsubstituted as well assubstituted groups. Exemplary substituents may include on or more, suchas 1, 2 or 3, of the following:

(1) alkyl, especially lower alkyl;

(2) alkoxy;

(3) hydroxy (or protected hydroxy);

(4) halo;

(5) (R¹²)(¹³)N--, such as amino (H₂ N--) ;

(6) alkylthio;

(7) mercapto;

(8) nitro;

(9) cyano;

(10) carboxy;

(11) carboalkoxy;

(12) carbocyclo, such as where said carbocyclo group is bonded through asingle bond, or is fused to said aryl group (e.g. to form atetrahydronaphthyl, indanyl or indenyl group), and wherein, in eachcase, the carbocyclo-aryl moiety so formed is bonded through the arylgroup; ##STR14##

where R¹⁷ is:

(a) hydrogen;

(b) alkyl, especially lower alkyl;

(c) aryl;

(d) heterocyclo;

(e) carbocyclo, such as cycloalkyl; or

(f) R¹⁷ may, together with R³, form an alkylene group of three to fivecarbons; ##STR15##

(17) phenyl;

(18) alkylcarbonyloxy, such as lower alkylcarbonyloxy;

(19) arylcarbonyloxy;

(20) arylthio;

(21) heterocyclooxy;

(22) aryloxy;

(23) alkylthio; or

(24) alkenyl.

The terms "arylcarbonyloxy" or "aroyloxy" denote an aryl group which isbonded through a carbonyl group which is, in turn, bonded through anoxygen bridge; the term "aryloxy" denotes on aryl group bonded throughan oxygen bridge; the term "arylcarbonyl" denotes an aryl group bondedthrough a carbonyl group; the term "arylaminocarbonyl" denotes an arylgroup bonded through an amino group which is, in turn, bonded through acarbonyl group; and the term "arylthio" denotes an aryl group bondedthrough a sulfur bridge.

The terms "halogen" or "halo", as employed herein alone or as part ofanother group, refer to chlorine, bromine, fluorine and iodine.

The terms "heterocyclo", "heterocyclic" or "heterocyclic ring system",as employed herein alone or as part of another group, denote anoptionally substituted, fully saturated or unsaturated, aromatic ornonaromatic cyclic group, for example, which is a 4 to 7 memberedmonocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclicring system, which has at least one heteroatom in at least one carbonatom-containing ring. Each ring of the heterocyclo group containing aheteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms,oxygen atoms or sulfur atoms, where the nitrogen and sulfur heteroatomsmay optionally be oxidized and the nitrogen heteroatoms may optionallybe quaternized. The heterocyclo group may be attached at any heteroatomor carbon atom.

Exemplary monocyclic heterocyclo groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazoyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, andtetrahydro-1,1-dioxothienyl, and the like.

Exemplary bicyclic heterocyclo groups include indolyl, benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, dihydroindazolylsuch as the group: ##STR16## furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), and the like.

Exemplary tricyclic heterocyclo groups include carbazolyl, benzindolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

It is understood that throughout this specification the terms"heterocyclo", "heterocyclic" and "heterocyclic ring system" denote bothunsubstituted as well as substituted groups. Exemplary heterocyclosubstituents may include one or more, such as 1, 2 or 3, of thefollowing:

(1) alkyl, especially lower alkyl;

(2) hydroxy (or protected hydroxy);

(3) halo;

(4) oxo (i.e. ═O);

(5) (R¹²)(R¹³)N--, such as amino (H₂ N--);

(6) alkoxy;

(7) carbocyclo, such as cycloalkyl;

(8) carboxy;

(9) heterocyclooxy;

(10) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;##STR17##

(12) mercapto;

(13) nitro;

(14) cyano;

(15) carboalkoxy;

(16) (R¹²)(R¹³)N--SO₂ --; ##STR18##

(19) aryl;

(20) alkylcarbonyloxy;

(21) arylcarbonyloxy;

(22) arylthio;

(23) aryloxy;

(24) alkylthio; or

(25) formyl.

The term "heterocyclooxy" denotes a heterocyclo group bonded through anoxygen bridge; and the term "heterocyclocarbonyl" denotes a heterocyclogroup bonded through a carbonyl group.

The term "hydroxyl protecting group", as used herein, denotes any groupknown as or capable of functioning as a hydroxyl protecting group, suchas those groups so described in "Protective Groups in Organic Synthesis"by T. W. Greene, John Wiley and Sons, 1991, or Fieser & Fieser.Exemplary hydroxyl protecting groups include benzyl, trialkylsilyl,acetate and benzoate.

The term "carboxy", as used herein alone or as part of another group,denotes the carboxylic acid group --COOH.

The term "amino acid", as used herein alone or as part of another group,preferably denotes the group: ##STR19## where R¹⁸ and R¹⁹ areindependently:

(1) hydrogen;

(2) alkyl, especially lower alkyl;

(3) alkenyl, especially lower alkenyl;

(4) aryl;

(5) heterocyclo;

(6) carbocyclo, such as cycloalkyl;

(7) R¹⁸ and R¹⁹ may be joined, together with the carbon atom to whichthey are bonded, to form a carbocyclo group, such as a 4- to 7-memberedcycloalkyl ring; or

(8) R¹⁸ and R²⁰ may be joined as described in the definition of R²⁰following;

R²⁰ is:

(1) hydrogen;

(2) alkyl, especially lower alkyl;

(3) aryl;

(4) heterocyclo;

(5) carbocyclo, such as cycloalkyl; or

(6) R¹⁸ and R²⁰ may be joined, together with the atoms to which they arebonded, to form a heterocyclic group, such as a 4 to 7 membered,saturated monocyclic heterocyclic ring which may be unsubstituted orsubstituted by groups such as:

(i) hydrogen;

(ii) alkyl, especially lower alkyl;

(iii) alkenyl, especially lower alkenyl;

(iv) aryl, for example, where said aryl group is bonded through a singlebond, or is fused to said monocyclic heterocyclic ring to form anunsaturated bicyclic heterocyclic ring system;

(v) heterocyclo;

(vi) mercapto;

(vii) alkoxy;

(viii) carbocyclo, such as cycloalkyl, for example, where saidcycloalkyl group is bonded through a single bond, or is fused orspirofused to said monocyclic heterocyclic ring to form a saturatedbicyclic heterocyclic ring system;

(ix) hydroxyl (or protected hydroxyl);

(x) aryloxy;

(xi) alkylthio;

(xii) arylthio; or

(xiii) oxo.

The amino acid moiety described above includes, for example, suchmoieties as may be found in D and L alanine, asparagine, aspartic acid,arginine, cysteine, glycine, glutamine, glutamic acid, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, serine,homoserine, threonine, tryptophan, tyrosine, valine, hydroxyvaline,norleucine, norvaline, phenylglycine, cyclohexylalanine, t-butylglycine(t-leucine), hydroxy-t-butylglycine, amino butyric acid, ornithine, andcycloleucine, and preferably, when R¹⁸ and R²⁰ are joined, together withthe atoms to which they are bonded, proline, 4-hydroxyproline,pyroglutamic acid, azetidine carboxylic acid, pipecolinic acid,indoline-2-carboxylic acid, tetrahydro-3-isoquinoline carboxylic acid,##STR20##

The term "peptide chain", as used herein, denotes two or more aminoacids as described above bonded through a peptide linkage ##STR21##

The "N-terminus" of the above-described amino acid(s) denotes the--N(R²⁰)-- group.

The term "salt(s)", as employed herein, denotes acidic and/or basicsalts formed with inorganic and/or organic acids and bases. Zwitterions(internal or inner salts) are included within the term "salt(s)" as usedherein, as are quaternary ammonium salts such as alkylammonium salts.The nontoxic, pharmaceutically acceptable salts are preferred, althoughother salts may be useful, for example, in isolation or purificationsteps which may be employed during preparation.

Exemplary acid addition salts include acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases such asdicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids suchas arginine, lysine and so forth. The basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g. methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

The present invention contemplates all compounds containing the moiety:##STR22## particularly such compounds capable of inhibiting retroviral,preferably HIV, protease.

Prodrugs and solvates of the inventive compounds are also contemplatedherein. The term "prodrug", as employed herein, denotes a compoundwhich, upon administration to a subject, undergoes chemical conversionby metabolic or chemical processes to yield a compound of the formula I,or a salt and/or solvate thereof. See H. Bundgaard, "Drugs of theFuture", 16 (5), 443-458 (1991); and H. Bundgaard (Ed), "Design ofProdrugs" 1985 Elsevier (Amsterdam), both incorporated herein byreference.

Solvates of the compounds of formula I are preferably hydrates.Tautomers of the inventive compounds are also contemplated, such ashemiketals of hydroxyketones, the enol form of ketones, and the like.

The initial definition provided for a group or term herein applies tothat group or term throughout the present specification, unlessotherwise indicated. It is to be understood that "exemplary" groupsrecited herein are illustrative and not limiting. It is particularlyadvantageous to employ those groups preceded by the terms "especially"or "preferably". Throughout this specification, groups and substituentsthereof may be chosen to provide stable moieties and compounds.

All stereoisomers of the present compounds are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations.

A description of exemplary methods for obtaining the compounds of thepresent invention follows. The reaction conditions of these methods,such as temperature, amount of reagent, pressure, reaction time,atmosphere and solvent employed may readily be ascertained by one ofordinary skill in the art.

In the following Reaction Schemes:

Q¹ and Q² are independently: ##STR23##

The above Q¹ and Q² groups are preferably employed where indicated asthey render the nitrogen atoms to which they are bonded non-basic. Wherecompounds of the invention are desired in which A^(a) and/or A^(b) areone of the above groups (1) to (7), the Q¹ or Q² groups of the followingReaction Schemes need not be removed. Where compounds of the inventionare desired in which A^(a) and/or A^(b) are other than the above groups(1) to (7), Q¹ or Q², for example, can be: ##STR24## (especiallyt-butoxycarbonyl (Boc) or carbobenzyloxy (Cbz)), forming amide andcarbamate groups, respectively. These latter groups can be removed, andreplaced with the desired A^(a) and/or A^(b) groups, by methods known inthe art. With the exception of the conditions used for their optionalremoval, Q¹ and Q² groups are chosen that are stable to the conditionsused in the following Reaction Schemes.

Q³ is:

(1) hydrogen; or

(2) alkyl.

The above Q³ groups are preferably employed where indicated as theyrender the nitrogen atom to which they are bonded basic. Exemplary Q³groups are hydrogen, unsubstituted lower alkyl, alkenyl-lower alkyl, andaryl-lower alkyl. Where compounds of the invention are desired in whichA^(c) is one of the above groups (1) or (2), the Q³ group employed inthe following Reaction Schemes need not be removed. Where compounds ofthe invention are desired in which A^(c) is other than the above groups(1) or (2), Q³ can, for example, be a benzyl group. The benzyl group maybe removed and replaced by the desired A^(c) group by methods known inthe art. With the exception of the conditions used for their removal, Q³groups are chosen that are stable to the conditions used in thefollowing Reaction Schemes.

In the following Reaction Schemes, where it is desired to remove Q¹, Q²and/or Q³ groups and to couple the amine groups so formed with anotherof the groups of A^(a), A^(b) and/or A^(c), methods known to those ofordinary skill in the art may be employed (as exemplified by Methods(D), (E) and (F) of Reaction Scheme 11). For examples of amineprotecting groups and their removal see Greene, "Protective Groups inOrganic Synthesis," John Wiley (1991). ##STR25##

Intermediate materials for the preparation of compounds of the formula Imay be prepared by Methods (A) or (B) as shown in Reaction Scheme 1above. Starting compounds II may readily be prepared by one of ordinaryskill in the art by known methods, such as those described in Greene.

In Method (A), an N-protected amino acid II is converted to a reactiveintermediate (not shown), such as to an acid chloride by reaction withthionyl chloride or oxalyl chloride, or to a mixed anhydride by reactionwith a chloroformate of the formula Cl--C(O)--OR²¹ where R²¹ is anunsubstituted lower alkyl group, and then treated with diazomethane togive the diazoketone III. Treatment of III with HCl gives theα-chloroketone IV, which may be converted to the chlorohydrin V byreduction, and then to the epoxide VI by reaction with a base by methodsknown in the art (see Handa et al., Eur. Pat. Appl. 346,847; Rich etal., J. Med. Chem., 34, 1222 (1991)). For example, the α-chloroketone IVmay be reduced with a hydride reducing agent such as lithium aluminumhydride, sodium borohydride, lithium and/or potassium-selectride,potassium borohydride, diisobutylaluminum hydride, and the like to givethe chlorohydrin V, which can be converted to the epoxide VI bytreatment with a base such as sodium or potassium hydroxide, sodium orpotassium hydride, or an alkylamine base such as triethylamine. CompoundIII may, alternatively, be treated with HBr to give the α-bromoketonecorresponding to α-chloroketone IV. The corresponding α-bromoketone maybe prepared or employed wherever the α-chloroketone IV is prepared oremployed in the present Reaction Schemes (for example, to prepare thebromohydrin corresponding to chlorohydrin V).

An alternate procedure, Method (B), based upon methods known in the art(see Desolms et al., European Patent 356,223) may also be employed. Thismethod involves reduction of the protected amino acid II to the alcoholVII using a reagent such as lithium aluminum hydride or borane (Brown etal., J. Amer. Chem. Soc., 82, 3866 (1960)) or via reduction of a mixedanhydride intermediate (formed as described above) with a hydridereducing agent such as sodium borohydride (Corey et al., J. Amer. Chem.Soc., 98, 6417 (1976)). The alcohol VII can be oxidized to the aldehydeVIII with a chromium (VI) reagent (Evans et al., J. Org. Chem., 47, 3016(1982)), or via a Moffatt (Albright et al., J. Org. Chem., 30, 1107(1965)) or Swern (Swern et al., J. Org. Chem., 43, 2480 (1978))procedure. The aldehyde VIII may be converted directly to the epoxide VIvia reaction with a sulfonium or arsonium ylide (Corey et al., J. Amer.Chem. Soc., 87, 1353 (1965); Still et al., J. Amer. Chem. Soc., 103,1283 (1981)), or indirectly by a Wittig or Peterson (Peterson, J. Org.Chem., 33, 780 (1968)) reaction to give the olefin IX, followed byepoxidation with a reagent such as meta-chloroperbenzoic acid (mCPBA),peracetic acid, or the like.

In Method (B), the aldehyde VIII may also be produced from a carboxylicacid ester of the acid II (not shown) by reduction withdiisobutylaluminum hydride (Ito et al., Chem. Pharm. Bull., 23, 3081(1975)), or via reduction of the methyl hydroxamate with lithiumaluminum hydride (Castro et al., Synthesis, 676 (1983)), and thealdehyde VIII converted to the epoxide VI as described above. ##STR26##

Reaction Scheme 2 above illustrates Methods (A) through (F), which maybe used to prepare compounds of the formula I where A^(a) is the same asA^(b) and D^(a) is the same as D^(b) ("symmetrical" compounds).

Method (A) begins by treating two equivalents of the epoxide VI with oneequivalent of Q³ --NH₂, where Q³ is preferably hydrogen, unsubstitutedlower alkyl, alkenyl-lower alkyl (e.g. allyl) or aryl-lower alkyl (e.g.benzyl), particularly benzyl as described above, and heating in asolvent such as methanol or dimethylformamide (Parker et al., Chem.Rev., 59, 737 (1959); for alternative conditions, see Posner et al., J.Amer. Chem. Soc., 99, 8208 (1977); Overman, J. Org. Chem., 50, 4154(1985); Tetrahedron Lett., 27, 2451 (1986)), giving the aminediol X.

The terminal groups Q¹ of the aminediol X may optionally be removed bymethods known to the skilled artisan (Greene), and the resultingbis-amine XI coupled to an N-protected amino acid or peptide chain(prepared using standard solid or solution phase techniques as describedin Bodanszky and Bodanszky, The Practice of Peptide Chemistry; pp.89-150, Springer-Verlag, 1984, where Q² is described above and iscompatible with the conditions used in the coupling reaction), using acoupling reagent such as dicyclohexylcarbodiimide (DCC),3-ethyl-3'-(dimethylamino)propylcarbodiimide (EDCI),bis-(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent), diphenylphosphoryl azide (DPPA) and the like, to give theaminediol XII. (For other methods see Bodanszky, Principles of PeptideSynchesis, pp. 9-58, Springer-Verlag (1984)). In the N-protected aminoacid or peptide chain, v is an integer from 1 to 4. Where, in thebis-amine XI, Q³ is hydrogen, the central nitrogen atom to which it isbonded ("central amine") may optionally be protected. Here, and in thefollowing Reaction Schemes where appropriate, the central amine may beprotected by nitrogen protecting groups known in the art, for example,by an aryl-alkyl group such as benzyl or trityl, an alkenyl-alkyl groupsuch as allyl, as well as groups forming, together with the centralnitrogen atom, a carbamate or amide group.

Methods (B) through (F), described following, illustrate alternateroutes for obtaining compound X, which may optionally be further treatedas described above in Method (A).

In Method (B), the process may be carried out in a step-wise fashion bytreatment of one equivalent of the epoxide VI with one equivalent or anexcess of the primary amine or ammonia (Q³ --NH₂) to give the aminoalcohol XIII, which in turn may be coupled again to the epoxide VI togive X.

In Method (C), the process may be carried out by reaction of twoequivalents of the chloroketone IV (or the corresponding bromoketone)with one equivalent of the aforementioned primary amine or ammonia (Q³--NH₂, where Q³ is preferably benzyl), to form the diketoamine XIV,which may be reduced to the aminediol X with a hydride reducing agentsuch as lithium aluminum hydride, sodium or potassium borohydride,lithium or potassium selectride (i.e., lithium or potassiumtri-sec-butylborohydride), diisobutylaluminum hydride, and the like.

In Method (D), a step-wise procedure can be carried out by coupling theaforementioned amino alcohol XIII with the chloroketone IV (or thecorresponding bromoketone) (Gordon et al., J. Org. Chem., 51, 3073(1986)) to give the ketohydroxyamine XV, which may be reduced by methodsdescribed above.

In Method (E), the epoxide VI may be opened with azide anion, such as bytreatment with sodium azide, to give the azidoalcohol XVI (Ingham etal., J. Org. Chem., 21, 373 (1956); Rosenberg et al., J. Med. Chem., 32,1371 (1989); Saito et al., Tetrahedron Lett., 30, 4153 (1989)). Theazido moiety may be reduced to the amine by, for example, hydrogenationover Pd/C or by treatment with triphenylphosphine (Vaultier et al.,Tetrahedron Lett., 24, 763 (1983)). The resulting aminoalcohol XVII canbe coupled to the epoxide VI, or to the chloroketone IV (or thecorresponding bromoketone) followed by reduction, as described above togive the aminodiol XVIII. The central amine may optionally be protectedas described above, and the Q¹ groups optionally removed and theresulting amines coupled to amino acids or peptide chains, also asdescribed above.

In Method (F), the aminoaldehyde VIII can be reacted with a vinylorganometallic reagent of the formula CH₂ ═CH(M), where M is ametal-containing moiety, such as vinyl lithium, vinyl magnesium bromideand the like to give the allylic alcohol XIX. The olefin moiety may beoxidatively cleaved to the aldehyde by ozonolysis, or the compound XIXconverted to the corresponding diol (not shown) with osmium tetraoxideor potassium permanganate, followed by cleavage of the diol with sodiumperiodate (Lemieux et al., J. Org. Chem., 21, 478 (1956)) to form thealdehyde. The aldehyde XX can then be reacted with the aminoalcohol XIIIunder reductive amination conditions (for example, hydrogenation overPd/C or reaction with sodium cyanoborohydride where Q³ is hydrogen orbenzyl; see Hudlicky, Reductions in Organic Chemistry, pp. 134-136, JohnWiley, 1984) to give compound X. ##STR27##

Reaction Scheme 3 above illustrates Methods (A) through (C), which maybe used to prepare compounds of the formula I where A^(a) differs fromA^(b) and/or D^(a) differs from D^(b) ("asymmetrical" compounds) byprocedures analogous to those of Reaction Scheme 2. In Reaction Scheme3, and hereinafter, the symbols "a" or "b" added to a moiety (e.g.R^(9a)) denote those groups ultimately forming a part of the moietyA^(a) -D^(a) - or A^(b) -D^(b) -, respectively, in the compounds offormula I, or, in the case of Q^(1a) or Q^(2a) and Q^(1b) or Q^(2b),denote those groups on the corresponding side of the molecule. Moietiesto which the symbols "a" or "b" are added are otherwise defined as above(e.g., R^(9a) is defined as for R⁹), although said moieties may bedefined independently of each other (e.g., R^(9a) may be definedindependently of R^(9b)).

Method (A) of Reaction Scheme 3 begins by coupling the aminoalcohol XIIIto the epoxide XXI (see Method (A) of Reaction Scheme 1 for preparationof epoxide XXI), or to the chloroketone XXII (see Method (A) of ReactionScheme 1 for preparation of chloroketone XXII; the correspondingbromoketone may also be prepared and employed as described therein)followed by reduction, to give the asymmetric aminediol XXIII.Optionally, the groups Q^(1a) and Q^(1b) may be sequentially removed andthe resulting amines coupled to N-protected amino acids or peptidechains to give the compound XXV. Where Q³ is hydrogen, the central amineto which it is bonded may optionally be protected as described above.

Such compounds as are prepared above may also be prepared by employingMethods (B) or (C) of Reaction Scheme 3 using procedures analogous tothose of Reaction Scheme 2. In particular, Method (B) of Reaction Scheme3 may be carried out by procedures analogous to those of Method (E) ofReaction Scheme 2; Method (C) of Reaction Scheme 3 may be carried out byprocedures analogous to those of Method (F) of Reaction Scheme 2. Theasymmetrical diols XXVI and XXIII may optionally be deprotected andcoupled as described above. Where Q³ is hydrogen, the central aminegroup no which it is bonded may, in each case, be optionally protectedas described above. ##STR28##

Reaction Scheme 4 above illustrates Methods (A) to (D) which may be usedto prepare compounds of the formula I where R¹ and/or R² are nothydrogen.

As shown above in Method (A), selective removal of the protecting group(Pro) of compound XXVIII (which compound may be prepared by methodsanalogous to those employed in the preparation of compound XIIIdescribed above) is conducted, where (Pro) is independently chosen fromthose groups defined for Q¹, followed by coupling of the resulting amineXXIX with epoxide VI, or chloroketone IV (or corresponding bromoketone)followed by reduction, giving the aminediol XXX. Optionally, where A^(c)is hydrogen, the central amine group to which it is bonded may beprotected as described above, and the Q^(1a) and/or Q^(1b) N-terminalgroups may then be sequentially or simultaneously removed and theresulting amines coupled to N-protected amino acids or peptide chains bymethods described above.

Alternatively, as shown in Method (B), the aldehyde XXXIII (see Method(B) of Reaction Scheme 1 for preparation) may be converted to the olefinXXXIV by Wittig or Peterson methodology, and the olefin XXXIV in turnepoxidized by methods analogous to those described above (see ReactionScheme 1, Method (B)) to yield compound XXXV. The epoxide XXXV may becoupled with the amine XXIX to give the aminediol XXXVI, whichoptionally may be protected at the central amine when A^(c) is hydrogenas described above, and the Q^(1a) and/or Q^(1b) N-terminal groups maybe sequentially or simultaneously deprotected and coupled to N-protectedamino acids or peptide chains to give aminediol XXXVIII.

The aminediol XXXVIII may also be prepared as shown in Method (C) byreaction of the aldehyde XXXIII with the vinyl organometallic reagentXXXIX, where M is a metal-containing moiety such as magnesium bromide,lithium, CeCl₂, and the like, to give the allylic alcohol XL. The doublebond may then be oxidatively cleaved by methods described above to givethe ketone XLI, which can then undergo reductive amination in thepresence of the amine XXIX, by methods also described above, to givecompound XXXVI. The compound XXXVI may be converted to the aminediolXXXVIII by the methods described above in Method (B). The reagent XXXIXemployed above in Method (C) may be prepared from the correspondingacetylene XLII via the vinyl bromide XLIII (Poller et al., Syn. Commun.,10, 805 (1980); Suzuki et al., Tetrahedron Lett., 24, 731 (1983)).

Alternatively, as shown in Method (D), the ketone XLI may undergoreductive amination by methods described above, in the presence ofammonia, to give the aminoalcohol XLIV, which in turn can undergoreductive amination in the presence of the ketone XLV (see Method (C)for a method for preparation thereof) to give the aminediol XLVI. Theaminediol XLVI may then be optionally protected, and sequentiallydeprotected and coupled to N-protected amino acids or peptide chains asdescribed above in Method (B) to give compound XLVII. ##STR29##

Reaction Scheme 5 above illustrates Methods (A) to (D), which may beused to prepare compounds of the formula I where R¹⁰ is not hydrogen.

In Method (A), the protected amino acid II can be converted to theketone XLVIII by methods known in the art (see, e.g., Gordon et al.,Tetrahedron Lett., 28, 1603 (1987)). For example, conversion of aminoacid II to an intermediate pyridyl ester or methyl hydroxamate (Weinrebet al., Tetrahedron Lett., 22, 3815 (1981)) (not shown), followed byreaction with an organolithium or organomagnesium reagent providesketone XLVIII. The ketone obtained may then be converted to the olefinXLIX via a Wittig or Peterson reaction, which can be followed byepoxidation using methods as described above. The epoxide L so formedmay be coupled with the aminoalcohol XXVII to give the aminediol LI.Optionally, the Q¹ groups may then be sequentially or simultaneouslydeprotected and coupled to N-protected amino acids or peptide chainsusing methods as described above to give compound LII.

Alternatively, as shown in Method (B), the olefin XLIX may be converteddirectly to the cis diol LIII using osmium tetraoxide or potassiumpermanganate (Kochi et al., Metal Catalyzed Oxidations of OrganicCompounds, pp. 162-171, 294-296, Academic Press (1981)), and the diolLIII in turn oxidized to the aldehyde LIV by methods described above.The aldehyde LIV may then undergo reductive amination in the presence ofthe aminoalcohol XXVII to give the aminediol LI, and the latter compoundconverted to the aminediol LII, by methods described above.

Another route is shown in Method (C). In Method (C), the epoxide L maybe coupled to a primary amine or ammonia Q³ -NH₂ by methods describedabove to give the aminoalcohol LV, which can be coupled to the epoxideLVI (see Method (A) for preparation thereof), to give the aminediolLVII. As described above, the Q¹ protecting groups may optionally besequentially or simultaneously removed and the resulting amino groupscoupled to N-protected amino acids or peptide chains to give compoundLVIII.

Alternatively, as shown in Method (D), the aminoalcohol LV may undergoreductive amination in the presence of the aldehyde LIX (see Method (B)for preparation) by methods described above to give compound LVII, andthe latter converted to compound LVIII by methods also described above,for example, in Method (C). ##STR30##

Reaction Scheme 6 above illustrates Methods (A), (B) and (C) which maybe used to prepare compounds of the formula I where R⁸ is not hydrogen.

In Method (A), the aminoalcohol XVII can be protected as shown yieldingcompound LX (Bergmann, Chem. Rev., 53, 309 (1953)) and the non-basicnitrogen alkylated (Benoiton et al., Can. J. Chem., 49, 1968 (1971)) bytreatment with a base such as sodium or potassium hydride, sodium orpotassium hexamethyldisilazide, or the like, followed by, for example,an alkylating agent such as an alkyl iodide, bromide, chloride,rosylate, triflate, or the like. Q^(1a) is an activating group whichrenders the hydrogen on the nitrogen atom to which it is bonded acidicand easily removed with a base as described above, such as a groupforming, together with --N(R^(8a)), a carbamate or amide group. Theaminoalcohol LXI formed can then be deprotected to form compound LXII,and the latter coupled to an epoxide XXI, or to a chloroketone XXII (thecorresponding bromoketone may be employed as described above) followedby reduction, by methods described above to give an aminediol LXIII,which optionally may be protected at the central amine and the Q¹ groupssequentially or simultaneously deprotected and coupled to N-protectedamino acids or peptide chains to give LXIV.

Alternatively, as shown in Method (B), an aminediol such as XXIIIa(which may be prepared from aminediol XXIII by methods known to one ofordinary skill in the art) may be monodeprotected at Q^(1a) or Q^(1b)and the resulting amine reacted under reductive amination conditions inthe presence of a compound of the formula R^(22a) --CHO where R^(22a) ishydrogen or alkyl, by methods described above to give LXV. Q⁴ is definedto include alkyl and those groups included in the definition of Q¹. Theresulting amine may be optionally coupled by methods described above togive compound LXVI. A similar process may optionally be carried out atthe other end of the molecule to produce an aminediol such as LXVII.

In Method (C), compounds where R⁸ is a methyl group may be prepared bydeprotecting an aminediol XXIIIa, where Q⁴ is not formyl; formylatingthe deprotected amine; and reducing the resulting formamide to themethylated amine using borane-dimethyl sulfide complex (Krishnamurthy,Tetrahedron Lett., 22, 3315 (1982)). The methylated amine LXV (R^(22a)═H) may optionally be coupled to an N-protected amino acid or peptidechain to give the compound LXVI (R^(22a) =H), and the compound LXVIconverted to compound LXVII (R²² =H) as described above. ##STR31##

Reaction Scheme 7 above illustrates Methods (A) to (E), which may beused to prepare compounds of the formula I where p and/or q are notzero.

In Method (A), the protected amino ester LXVIII (R²³ may beunsubstituted lower alkyl, aryl or aryl-lower alkyl) where p_(a) =1-4and q=0 can be alkylated via its enolate anion (formed by treatment ofthe ester with a base such as lithium diisopropylamide, lithiumbis(trimethylsilyl)amide or the like) with R^(9a) - X, where X ishalogen, rosylate, mesylate or the like to give the ester LXIX. Theester may be reduced directly to the aldehyde LXX withdiisobutylaluminum hydride or in two steps by conversion to the primaryalcohol with a hydride reducing agent and then oxidation to the aldehydeas described above. The aldehyde can be converted directly to theepoxide LXXI via reaction with a sulfonium or arsonium ylide or by aWittig or Peterson reaction to give the corresponding olefin (notshown), followed by epoxidation as described above. The epoxide may becoupled to the amino alcohol XXVII to give the aminediol LXXII, whichoptionally may then be sequentially or simultaneously deprotected andcoupled to N-protected amino acids or peptide chains as described aboveto give the compound LXXIII. The starting ester LXVIII of Method (A) maybe obtained by methods known to those skilled in the art such as thosemethods described in J. March, "Advanced Organic Chemistry", John Wiley(1985) (see pages 1157-1158).

Method (B) illustrates a method for obtaining compounds where both p_(a)and p_(b) >zero. In this method, the epoxide LXXI is reacted withammonia or a primary amine Q³ --NH₂ to give the compound LXXIV, followedby coupling with the epoxide LXXV (which may be prepared by a methodanalogous to that for preparing the epoxide LXXI above) to give compoundLXXVI. The compound LXXVI may optionally then be sequentially orsimultaneously deprotected and coupled to N-protected amino acids orpeptide chains as described above.

Method (C) illustrates a method for obtaining compounds where q_(a) =2-4and p=zero. In Method (C), Wittig reaction of the hydroxyphosphoraneLXXVII with the protected amino aldehyde XXXIII gives the olefin LXXVIIIwhich can be reduced to the saturated alcohol LXXIX under catalytichydrogenation conditions. Oxidation of the alcohol LXXIX to the aldehydeLXXX may be followed by conversion to the epoxide LXXXI, the latterachieved by a Wittig reaction followed by treatment withm-chloroperoxybenzoic acid (mCPBA). The epoxide LXXXI is then coupledwith the amino alcohol XXVII to give the aminediol LXXXII as describedabove. The aminediol may then optionally and sequentially be deprotectedand coupled to N-protected amino acids or peptide chains to givecompound LXXXIII. The hydroxyphosphorane starting material LXXVII may beprepared by reaction of the appropriate haloalcohol withtriphenylphosphine under standard conditions.

Method (D) illustrates a method where compounds in which q_(a) and q_(b)are both >1 and p=0 may be prepared by reaction of the epoxide LXXXIwith ammonia or a primary amine Q³ --NH₂ to give compound LXXXIV. Thelatter compound may then be coupled with the epoxide LXXXV (prepared,e.g., by the method employed above for preparation of the epoxide LXXXI)to yield the aminediol LXXXVI. The aminediol LXXXVI may optionally thenbe sequentially or simultaneously deprotected and coupled to N-protectedamino acids or peptide chains as described above.

Method (E) illustrates a method for preparing intermediate compoundswhich may be employed in preparing aminediols where q=1 and p=0. InMethod (E), the intermediate aldehyde LXXXVIII may be prepared by anArndt-Eistert reaction (Meier and Zeller, Angew. Chem. Int. Ed. Engl.,14, 32 (1975)) on the diazoketone III to give the carboxylic acidLXXXVII. Conversion of the carboxylic acid to the aldehyde may beconducted by reduction and oxidation as described above. The aldehydemay then be converted to the desired aminediol as described in Methods(C) and (D). ##STR32##

Reaction Scheme 8 illustrates a method for the preparation of compoundsof the formula I where R^(9') is not hydrogen.

An N-protected amino acid II may be converted into an acetal LXXXIXwhere R²⁴ and R²⁵ are independently hydrogen or unsubstituted loweralkyl as shown. Treatment of the acetal LXXXIX with a base such aslithium diisopropyl amide, followed by reaction with a compound R^(9')-Y where Y may be Cl, Br, I or triflate, and hydrolysis of the acetalgives the α-substituted amino acid XC. The amino acid XC may beconverted to amine diols of the formula I by those methods described inSchemes 1 to 7 above. Unnatural, optically active α-amino acids can beprepared by methods such as those described in Evans et al., J. Am.Chem. Soc., 112, 4011 (1990); and Oppolzer et al., Tetrahedron Lett.,30, 5603, 6009 (1989). Alternative methods are also described inWilliams, R. M., Synthesis of Optically Active α-Amino Acids, PergamonPress: Oxford (1989). ##STR33##

Intermediate materials for the preparation of compounds of the formula Imay alternatively be prepared by Methods (A) to (F) as shown in ReactionScheme 9 above.

In this regard, the present invention provides a novel method for thepreparation of a halohydrin of the following formula: ##STR34## whereQ¹, E, R², R⁸, R⁹, R^(9') and R¹⁰ are as defined above, particularlywhere R⁹ is not the same as R^(9') (most preferably, where one of R⁹ orR^(9') is hydrogen), and X_(hal) is chloro or bromo, comprising the stepof contacting an olefin of the following formula: ##STR35## with thecompound HOX_(hal).

The compound HOX_(hal) may be formed in situ for use in the method ofthe present invention, such as by contacting N-chlorosuccinimide,N-bromosuccinimide, Br₂ or Cl₂ with water. Preferred molar ratios of thecompound HOX_(hal) to the olefin starting material are from about 1:1 toabout 3:1.

In a preferred embodiment, the novel method of the present inventioncomprises the optional further step of preparing an epoxide of thefollowing formula: ##STR36## by contacting the above halohydrin with abase.

The base employed may be any basic compound providing conversion of thehalohydrin to the epoxide, such as alkali metal (e.g., sodium orpotassium) hydroxides, alkali metal (e.g., sodium or potassium)hydrides, alkali metal (e.g., sodium or potassium) carbonates, or aminebases (e.g., trialkylamines). Preferred molar ratios of the base to thehalohydrin are from about 1:1 to about 5:1.

The temperature employed during the above steps for halohydrin and,optionally, epoxide formation is preferably from about -78° C. to about50° C. The steps are preferably conducted in an organic solvent such asdioxane or tetrahydrofuran. An alcohol (for example, methanol) ispreferably employed during epoxide formation, such as by addition to theaforementioned organic solvent when a single pot is employed,particularly where the base is other than an amine base. Times employedare those sufficient for halohydrin and, optionally, epoxide formation.

The above novel method of the present invention preferentially (that is,in a greater than 1:1 molar ratio) provides halohydrins of the followingrelative stereoconfiguation: ##STR37## relative to the correspondingstereoisomers thereof: ##STR38## Thus, the above method of the presentinvention comprising the preferred further step of epoxide formation isparticularly advantageous where epoxides having the following relativestereoconfiguration are sought: ##STR39## as such compounds are formedpreferentially (that is, in a greater that 1:1 molar ratio) relative tothe corresponding stereoisomers thereof: ##STR40## The starting olefinsmay be prepared by methods such as those described by Luly et al., J.Org. Chem., 52, 1487-1482 (1987).

Method (A) illustrates the novel method of the present invention. InMethod (A), olefin IX is converted to the halohydrin (not shown) bytreatment with aqueous bromine or N-bromo-succinimide orN-chlorosuccinimide, and then treated with base, such as potassiumcarbonate or potassium or sodium hydroxide or the like to give epoxideVI.

As shown in Method (B), olefin IX may be converted to the diol XCI bytreatment with osmium tetroxide or potassium permanganate, or othermethods known in the art (Kochi, et al., Metal Catalyzed Oxidations ofOrganic Compounds, pp. 162-171, 294-296, Academic Press (1981);Jacobsen, et al., J. Am. Chem. Soc., 110, 1968 (1988); Sharpless, etal., J. Org. Chem., 57, 2768 (1992)). Diol XCI may be treated with asulfonyl chloride (e.g., methanesulfonyl chloride or p-toluenesulfonylchloride; Ar denotes aryl) to give the sulfonate XCII; or,alternatively, the primary hydroxyl group of XCI may be selectivelyprotected (see Greene, Protective Groups in Organic Synthesis), and thesecondary hydroxyl group sulfonylated, followed by deprotection of theprimary hydroxyl group, to give XCIII. The sulfonate esters XCII orXCIII may be independently converted to the epoxide VI by treatment withbase, such as sodium or potassium hydroxide, or an alkylamine base suchas triethylamine; the latter reaction from XCIII occurs with inversionof the configuration of the secondary hydroxyl group.

In Method (C) (see Thompson, et. al., J. Am. Chem. Soc., 115, 801 (1993)and Bennett, et. al., JCS Chem. Commun., 737 (1993)), the olefin XCIVmay be converted to the epoxide XCV by asymmetric epoxidation (Gao, etal., J. Am. Chem. Soc., 109, 5765 (1987)). Starting olefin XCIV mayreadily be prepared by one of ordinary skill in the art by known methods(e.g., Witrig reaction, March, Advanced Organic Reactions, pp 839-841and pp 845-854 (Third Edition)). Epoxide XCV can be converted to theazidodiol XCVI by treatment with azide anion, such as treatment withsodium azide and titanium bisisopropoxide (Caron, et al., J. Org. Chem.,53, 5185 (1988); Omaka, et al., Chem. Lett., 1327 (1986)). The azidodiolcan be reduced by methods described above in Reaction Scheme 2, Method(E) to give the aminodiol XCVII. Protection of the amine by methodsknown in the art, such as those described in Greene, Protective Groupsin Organic Synthesis, may provide Compound XCI.

Alternatively, as described in Method (D), azidodiol XCVI may beconverted to the mixture of haloacetates XCVIII and XCIX by treatmentwith 2-acetoxyisobutyryl halide, or treatment with trimethylorthoacetate and PPTs followed by acetyl halide (e.g., acetyl bromide)or trimethylsilyl halide (e.g., trimethylsilyl chloride) (Russel, etal., J. Am. Chem. Soc., 95, 4025 (1973); Thompson, et al., ibid, 115,801 (1993); Kolb, et al, Tetrahedron, 48, 10515 (1992)). Thehaloacetates XCVIII and XCIX may be treated with base such as sodiummethoxide or sodium or potassium carbonate, to give the azidoepoxide C.Reduction of the azidoepoxide C to the aminoepoxide CI followed byprotection of the amine by methods known in the art provides epoxide VI.

Alternatively, as shown in Method (E), the azidodiol XCVI may beconverted to the epoxide C by methods analogous to those described above(Reaction Scheme 9, Method (B)).

In Method (F), diol XCI may be converted to the cyclic sulfate CXXIV bytreatment, first with thionyl chloride to give the cyclic sulfite(structure not shown), and then oxidation with potassium permanganate orruthenium trichloride/sodium periodate, and the like (Lohray, Synthesis,1035 (1992); Gao, et al., J. Am. Chem. Soc., 110, 7538 (1988)). CompoundCXXIV, or the intermediate sulfite, may be converted to aminediols bymethods described above for the conversion of epoxides VI and/or XXI.##STR41##

Reaction Scheme 10 above illustrates Methods (A) through (C), which maybe used to prepare compounds of the formula I where A^(a) is the same asA^(b) and D^(a) is the same as D^(b) ("symmetrical" compounds.

In Method (A), one equivalent of the bis-amine CXXIV (prepared as for XIwhere A^(c) replaces Q³) is coupled to a carboxylic acid (prepared bystandard techniques, where R³ is described above and is compatible withthe conditions used in the coupling reaction), using a coupling reagentsuch as DCC, EDCI, BOP reagent, BOP-C1, DPPA, and the like, as describedearlier (for alternative coupling conditions see Bodanszky, "Principlesof Peptide Synthesis"; pp. 9-58, Springer-Verlag, (1984)) to give theaminediol CII. Where, in the bis-amine CXXIV, A^(c) is hydrogen, thecentral amine to which it is bonded may optionally be protected asdescribed above.

In Method (B), the process may be carried out in a step-wise fashion.The groups Q^(1a) and Q^(1b) in CXXV (prepared as for XXIII where A^(c)replaces Q³) may be sequentially removed and the resulting aminescoupled to a carboxylic acid to give the compound CII. Where A^(c) ishydrogen, the central amine to which it is bonded may optionally beprotected as described above.

Method (C) begins with removal of the group Q^(1a) and coupling of theresulting amine with a carboxylic acid to give the azidoalcohol CIII.The azido moiety may be reduced and the resulting aminoalcohol CIV canbe coupled to the epoxide XXI or the haloketone XXII, followed byreduction, to give the aminediol CV (see Reaction Scheme 3). The centralamine may optionally be protected with A^(c). Removal of the groupQ^(1b) and coupling with a carboxylic acid as described above gives CII.##STR42##

Reaction Scheme 11 above illustrates Methods (A) through (F) which maybe used to prepare compounds of the formula I where A^(a) differs fromA^(b) and/or D^(a) differs from D^(b) ("non-symmetrical" compounds).

According to Methods (A) and (B), non-symmetrical compounds may beprepared by procedures analogous to those of Scheme 10. In Method (A),the groups Q^(1a) and Q^(1b) may be sequentially removed and theresulting amines coupled to carboxylic acids to give Compound CVI. WhereA^(c) is hydrogen, the central amine to which it is bonded mayoptionally be protected as described above. Such compounds may also beprepared by employing Method (B), starting from azidoalcohol XVI andusing procedures analogous to those of Method (C) of Reaction Scheme 10.

According to Method (C), non-symmetrical compounds may be prepared byprocedures analogous to those of Reaction Schemes 2, 3 and 10. Themethod begins by removing the group Q^(1a) and coupling the resultingamine to N-protected amino acids or peptide chains to give the compoundCIX. The azido moiety may be reduced and the resulting aminoalcohol CXcan be coupled to the epoxide XXI, or to the haloketone XXII followed byreduction, as described in Methods (C) through (E) of Reaction Scheme 2,to give the aminodiol CXI. Optionally, the central amine may beprotected and the Q^(1b) group may be removed and the resulting aminecoupled to a suitable carboxylic acid by procedures analogous to thoseof Method (A) of Reaction Scheme 10 to give the aminodiol CXII.

Method (D) starts from compound CXIII (prepared as for XXIV where A^(c)replaces Q3) where w=0-4. The hydroxyl groups may optionally beprotected such as with an ethoxyethyl group as described in Greene,Protective Groups in Organic Synthesis (P_(hyd) denotes a hydroxylprotecting group). The Q^(2b) group may then be removed and theresulting amine CXIV coupled with a chloroformate to afford, afterremoval of the hydroxyl protecting groups, the carbamate CXV. WhereA^(c) is hydrogen, the central amine to which it is bonded may beprotected as described above.

In Method (E), the amine CXIV may be coupled with an isocyanate compoundor a carbamoyl chloride to provide, after removal of the hydroxylprotecting groups, the urea CXVI. Where A^(c) is hydrogen, the centralamine to which it is bonded may be protected as described above.

In Method (F), the amine CXIV may be coupled with a carboxylic acid,using methods described in Scheme 10, to give, after removal of thehydroxyl protecting groups, the amide CXVII. Where A^(c) is hydrogen,the central amine to which it is bonded may optionally be protected asdescribed above. ##STR43##

Reaction Scheme 12 above illustrates Methods (A) and (B) which may beused to prepare compounds of the formula I where R⁹ is a substituted(hydroxyphenyl)methyl group.

Compound CXVIII in which the nitrogens bear P^(1a) or P^(1b) (P¹ denotesa nitrogen protecting group) and in which the hydroxyl groups areprotected (P2 denotes a hydroxyl protecting group) of Method (A) may beprepared by methods described in Greene, Protective Groups in OrganicSynthesis. In particular, the aforementioned nitrogen and hydroxyloxygen may be connected by a one carbon linker to form an oxazolidinering. The phenol may then be reacted with a suitable alcohol CXIX (whereR²⁶ is a lower alkyl group) in the presence of a phosphine (e.g.,triphenylphosphine) and a reagent, such as diethyl- ordiisopropylazodicarboxylate to give, after deprotection, the substitutedphenol CXXI (Mitsunobu, Synthesis, 1 (1981); Varasi, et al., J. Org.Chem., 52, 4235 (1987)). Alternatively, phenol CXVIII may be treatedwith a base, such as potassium carbonate, sodium or potassium hydride,sodium or potassium bis(trimethylsilyl)amide, or the like, and asuitable activated alkyl compound CXX where X can be a halogen, such asbromo, chloro, or iodo, or a sulfonate ester such as trifluoromethylsulfonate (i.e. --O--SO₂ --CF₃) to give CXXI. Compound CXX can beprepared by methods known to those skilled in the art.

The aminediol CXXI may also be prepared as shown in Method (B).Procedures analogous to those of Method (A) above may be used to convertphenol CXXII (see Reaction Scheme 1 and Methods (A) and (B) of ReactionScheme 9 for preparation) to epoxide CXXIII. Compound CXXIII may beconverted to aminediol CXXI by procedures analogous to those of Methods(A), (B) and (E) of Reaction Scheme 2 and Methods (A) and (B) ofReaction Scheme 3.

Compounds of the formula I where R¹¹ is not hydrogen may be obtained,for example, by methods known in the art for adding a hydroxylprotecting group, such as those described in Greene (referred to above).

Modifications to the processes of the above Reaction Schemes 1 to 12 maybe made by one of ordinary skill in the art to obtain any of thecompounds of the present invention. For example, protection anddeprotection of groups may be suitably employed during such preparation.

PREFERRED COMPOUNDS

Preferred compounds of the formula I are those compounds containing thepreferred groups described following.

A^(a) and A^(b) are preferably, independently,

(A) hydrogen;

(B) alkyl such as unsubstituted lower alkyl or hydroxyalkyl;

(C) the group: ##STR44## where Z is sulfur or, most preferably, oxygen;R³ is preferably alkyl such as unsubstituted lower alkyl (e.g., methylor tert-butyl), arylalkyl (e.g., benzyl), or heterocycloalkyl (e.g.,pyridylmethyl or benzimidazolylmethyl); and

R⁴ is preferably alkyl such as unsubstituted lower alkyl (e.g., methyl)or, most preferably, R⁴ is hydrogen;

(D) the group: ##STR45## where R⁵ is preferably hydrogen; carbocyclo(e.g., indenyl); alkyl such as unsubstituted lower alkyl (e.g., methyl,ethyl or tert-butyl) or alkyl which is substituted by one or more ofamino, substituted amino (e.g., amino substituted by formyl, phenyl,benzyl or benzyloxycarbonyl), halo (e.g., fluoro), aryl (e.g., phenyl),hydroxy (e.g., mono or dihydroxy) or protected hydroxy, heterocyclo(e.g., dihydroindazolyl (optionally substituted by oxo and/or benzyl)),alkoxy (such as unsubstituted lower alkoxy (e.g., methoxy) or arylalkoxy(e.g., benzyloxy)), aryloxy (e.g., phenoxy), or arylaminocarbonyl (e.g.,phenylaminocarbonyl); aryl (e.g., phenyl or biphenyl); heterocyclo(e.g., imidazolyl (optionally substituted by trityl and/or phenyl),oxazolyl (optionally substituted by phenyl), 2- furo[2,3-c]pyridinyl,2-furo [3,2-b]pyridinyl, 2-furo[2,3-b]pyridinyl, quinoxalinyl,benzothiazolyl, quinolinyl, benzimidazolyl (optionally substituted bybenzyloxymethyl), pyridyl, indolyl, oxazolidinyl (optionally substitutedby oxo), dihydroisoindolyl (optionally substituted by oxo),1,3-dioxolane (optionally substituted by methyl groups),dihydroquinazolinyl (optionally substituted by oxo), or benzoxazolyl);or alkynyl (e.g., phenylalkynyl); R⁵ is most preferably hydrogen, alkyl(unsubstituted or substituted, in the latter case preferablyhydroxyalkyl), aryl or heterocyclo;

R⁶ and R⁷ are preferably hydrogen, or alkyl such as unsubstituted loweralkyl (e.g., methyl) or hydroxyalkyl; or

two of R⁵, R⁶ and R⁷, together with the carbon atom to which they arebonded, form a carbocyclo group (e.g., cyclobutyl or cyclopentyl(optionally substituted by hydroxy), or indanyl (optionally furthersubstituted by hydroxy or protected hydroxy)), or a heterocyclo group(e.g., oxetanyl, tetrahydrofuryl (optionally substituted by hydroxy),tetrahydro-1,1-dioxothienyl, tetrahydropyranyl, or benzimidazolyl(optionally substituted by methyl));

(E) the group: ##STR46## where z is sulfur or, most preferably, oxygen;

R³ is preferably hydrogen; aryl (e.g., phenyl or naphthyl); alkyl whichis unsubstituted (e.g., ethyl or tert-butyl) or substituted by one ormore of oxo, hydroxy (e.g., mono- or dihydroxy) or protected hydroxy,aryloxy (e.g., phenoxy or naphthyloxy), alkoxy (e.g., methoxy,benzyloxy, or benzimidazolylpropoxy), aryl (e.g., phenyl ), heterocyclo(e.g., benzimidazolyl, 1,3-dioxolane (optionally substituted by methylgroups) , indolyl, pyridyl, or dihydroindazolyl (optionally substitutedby oxo)), oxime, alkoxyimino (e.g., methoxyimino), amino or substitutedamino (e.g., benzyloxycarbonylamino), alkylaminocarbonyl (e.g.,N-methylaminocarbonyl), arylaminocarbonyl (e.g., phenylaminocarbonyl),alkylaminocarbonyloxy (e.g., N-methylaminocarbonyloxy), or fluoro (e.g.,to form trifluoromethyl); carbocyclo (e.g., cyclopentyl or cyclohexyl(optionally substituted by methyl and/or hydroxy groups), or indanyl(optionally further substituted by hydroxy); or heterocyclo (e.g.,quinolinyl, pyrrolidinyl (optionally substituted by methyl and/or oxogroups), oxazolidinyl (optionally substituted by methyl and/or oxogroups), dihydroisoindolyl (optionally substituted by formyl),tetrahydrofuryl (optionally substituted by hydroxy and/or methylgroups), or benzimidazolyl); R³ is most preferably carbocyclo or alkylwherein the carbocyclo or alkyl groups are substituted, particularly byone or more of hydroxy, aryl, heterocyclo, alkylaminocarbonyl or fluoro(especially to form trifluoromethyl); or

(F) the groups:

R³ --SO₂ --or

R³ --SO--

where R³ is alkyl, especially unsubstituted lower alkyl.

The above groups (C), (D) and (E) are most preferred as A^(a) or A^(b)substituents.

A^(c) is most preferably hydrogen. Where A^(c) is other than hydrogen,preferred A^(c) groups are alkyl--O--C(O)--, such astrialkylsilylalkyl--O--C(O)-- (e.g., trimethylsilylethoxycarbonyl),fluorenylalkyl--O-C(O)-- (e.g., fluorenylmethoxycarbonyl) orarylalkyl--O--C(O)-- (e.g., benzyloxycarbonyl); arylalkyl (e.g.,benzyl); or unsubstituted lower alkyl (e.g., methyl).

E is preferably a single bond or a peptide chain containing 1 or 2 aminoacids. Preferred amino acids are those wherein, in the formula:##STR47## R¹⁸ is hydrogen or unsubstituted lower alkyl (e.g., methyl);R¹⁹ is hydrogen, aryl (e.g., phenyl) , or, most preferably, R¹⁹ is loweralkyl which is unsubstituted (e.g., methyl, isopropyl, or tert-butyl) orwhich is substituted, particularly by one or more of hydroxy (orprotected hydroxy), amino, aminocarbonyl, fluoro (e.g., to formtrifluoromethyl), phenyl, or hydroxyphenyl; or

R¹⁸ and R¹⁹, together with the carbon atom to which they are bonded,form a cycloalkyl group (e.g., cyclopentyl); and

R²⁰ is hydrogen or unsubstituted lower alkyl (e.g., methyl).

R¹ and R² are most preferably hydrogen. Where R¹ and R² are other thanhydrogen, preferred R¹ and R² groups are arylalkyl (e.g., benzyl).

R⁸ is preferably hydrogen; alkyl, especially unsubstituted loweralkyl(e.g., methyl); R⁸ and R⁹, together with the atoms to which thesegroups are bonded, form a heterocyclo group (e.g., pyrrolidinyl ortetrahydroisoquinolinyl); R⁸ and R¹¹, together with the atoms to whichthese groups are bonded, form a heterocyclo group (e.g.,2,2-dimethyloxazolidinyl); or R⁸ and A^(a) or A^(b) (as describedabove), together with the atoms to which these groups are bonded, form aheterocyclo group (e.g., 5,5-dimethyl-2-oxo-oxazolidinyl). R⁸ is mostpreferably hydrogen.

R⁹ is most preferably alkyl, especially unsubstituted lower alkyl (e.g.,sec-butyl or isobutyl); or substituted lower alkyl, particularly:

(A) cycloalkylalkyl (e.g., cyclohexylmethyl);

(B) heterocycloalkyl, especially heterocyclomethyl (e.g., indolylmethyl,pyridylmethyl, or quinolinylmethyl);

(C) arylalkenylalkyl, particularly where aryl is substituted by a groupAr(sub) defined below; or

(D) arylalkyl, for example, phenylethyl, or, especially, a group of theformula: ##STR48## where Ar (sub) is:

(i) hydrogen;

(ii) hydroxy;

(iii) alkenyl (e.g., ethenyl);

(iv) unsubstituted lower alkyl (e.g., ethyl); or

(v) alkoxy, especially:

unsubstituted lower alkoxy (e.g., methoxy);

alkoxyalkoxy (e.g., methoxyethoxy, methoxybutoxy, benzyloxyethoxy, orbenzyloxypropoxy);

hydroxyalkoxy (e.g., hydroxyethoxy, hydroxypropoxy, or hydroxybutoxy);

arylalkoxy (e.g., benzyloxy);

heterocycloalkoxy (e.g., morpholinylpropoxy, morpholinylethoxy,3-oxo-morpholinylethoxy, pyridylethoxy, benzoxazolylmethoxy,benzoxazolylpropoxy, imidazolylethoxy, 2-oxo-oxazolidinylethoxy,3-methyl-2-oxoimidazolidinylethoxy, 2-hydroxy-2-pyridylethoxy);

aminoalkoxy (e.g., aminoethoxy) or aminocarbonyloxyalkoxy (e.g.,aminocarbonyloxyethoxy), especially where the amino moiety isunsubstituted or mono- or disubstituted by alkyl (e.g., methyl) or aryl(e.g., tolyl);

heterocyclocarbonylalkoxy (e.g., morpholinylcarbonylethoxy,morpholinylcarbonylmethoxy or piperidinylcarbonylmethoxy);

heterocyclooxyalkoxy (e.g., pyridyloxyethoxy);

alkoxycarbonylalkoxy (e.g., ethoxycarbonylmethoxy); or

carboxyalkoxy (e.g., carboxymethoxy).

Where R⁹ is other than alkyl, preferred R⁹ groups are hydrogen; aryl;alkenyl; carbocyclo; or R⁹ and R⁸, together with the atoms to whichthese groups are bonded, form aheterocyclo group (e.g., pyrrolidinyl ortetrahydroisoquinolinyl).

R^(9') is preferably hydrogen.

R¹⁰ is most preferably hydrogen. Where R¹⁰ is other than hydrogen,preferred R¹⁰ groups are arylalkyl (e.g., benzyl); unsubstituted loweralkyl (e.g., methyl); or R¹⁰ and R¹¹ together form a keto group.

R¹¹ is most preferably hydrogen. Where R¹¹ is other than hydrogen,preferred R¹¹ groups are alkoxyalkyl (e.g., ethoxyethyl); unsubstitutedlower alkyl (e.g., methyl); R¹¹ and R⁸, together with the atoms to whichthese groups are bonded, form a heterocyclo group (e.g.,2,2-dimethyloxazolidinyl); or R¹¹ and R¹⁰ together form a keto group.

p and q are preferably 0.

Particularly preferred compounds of the present invention are thefollowing compounds, and salts and/or stereoisomers thereof, prepared asthe title compounds of the following Examples of this specification: 2,21, 76, 93, 104, 162, 175, 178, 209, 224, 226, 234, 246, 257, 262, 271,282, 293, 297, 298, 304, 308, 311, 322, 327, 331, 333, 334, 336, 339,344, 352, 355, 356, 359, 366, 368, 377 and 383.

PREFERRED UTLIITY

Proteases are enzymes which cleave proteins at specific peptide bondsand, in living systems, mediate or control a broad spectrum ofbiological functions, such as cleaving precursors to form activeproteins in post-translational processing of polypeptides. For example,retroviral proteases cleave large precursor polypeptides, produced ininfected cells, into smaller protein components, or subunits, which aresubsequently assembled to form functional virus structures. As proteasesencoded by the viral genome play a critical role in the replication of avirus, these enzymes represent targets for therapeutic agents.

Retroviruses are viruses which contain two copies of their RNA genome,each of which is copied into a double strand of DNA using a retroviralenzyme reverse transcriptase (RT). A second retroviral enzyme,ribonuclease H, is part of the RT protein and facilitates the synthesisof the DNA:DNA duplex. A third retroviral enzyme called integrasesplices the double stranded DNA copy of the virus into the chromosome ofthe host cell. A fourth retroviral enzyme cell protease is critical tothe process of viral replication by cleaving polypeptide precursors intorequired enzymes and structural proteins.

The compounds of the present invention inhibit retroviral proteases,thereby inhibiting viral replication, and are thus especially useful inthe treatment and/or prevention of retroviral infections caused by suchpathogenic organisms.

Exemplary protease-encoding retroviruses, the replication of which maybe inhibited by the compounds of the present invention include the humanT-cell lymphotrophic viruses, HTLV-I and HTLV-II, the humanimmunodeficiency viruses, for example, HIV-1, HIV-2 or mutants thereof(AIDS pathogens), feline leukemia virus and simian immunodeficiencyvirus. Protease inhibition may be assayed by methods such as thosedescribed below in the Examples section of the present specification.The compounds of the present invention may, of course, be used tosimultaneously inhibit the replication of two or more retroviruses, aswell as to inhibit the replication of a single retrovirus.

The compounds of the present invention are particulary useful in theinhibition of human immunodeficiency virus (HIV) protease, and thus inthe prevention and/or treatment of infection by HIV viruses (HIV-1,HIV-2, and mutants thereof), including the treatment of consequentpathological conditions such as AIDS.

HIV protease is a retroviral protease which processes the gagpolyprotein precursor into core proteins and the pol polyproteinprecursor into reverse transciptase, integrase, and the protease itself.HIV protease is essential for the correct processing of thesepolyproteins and the production of infectious viral particles, asevidenced by the fact that mutations of the protease gene result innon-infectious viral particles with an immature morphology. Inhibitionof HIV protease is thus a highly attractive target for anti-HIV therapy.

Use of the compounds of the present invention in inhibiting HIV proteaseincludes, but is not limited to, treating a wide range of states of HIVinfection such as treating or preventing AIDS or ARC (AIDS relatedcomplex), treating both symptomatic and asymptomatic HIV-infectedpatients, and treating actual or potential exposure to HIV. For example,the compounds of this invention are useful in treating infection by HIVafter suspected past exposure to HIV by, e.g., blood transfusion,accidental needle stick, or exposure to patient blood during surgery.

As indicated above, the compounds of the present invention may also beuseful in the treatment and/or prevention of infections caused by otherretroviruses. Exemplary retroviruses that are pathogenic in man inaddition to the human immunodeficiency viruses are HTLV-1 and HTLV-2.Exemplary viruses pathogenic in other species are feline leukemia virusand simian immunodeficiency virus.

The present invention also provides pharmaceutical compositionscomprising at least one of the inventive compounds capable of inhibitingretroviral protease in an amount effective therefor, and apharmaceutically acceptable vehicle or diluent. The compositions of thepresent invention may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration. The compounds may, for example, be administered orally,such as in the form of tablets, capsules, granules or powders;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection or infusion techniques (e.g. as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasallysuch as by inhalation spray; or rectally such as in the form ofsuppositories; in dosage unit formulations containing non-toxic,pharmaceutically acceptable vehicles or diluents. The present compoundsmay, for example, be administered liposomally.

When administered orally, the compositions may be prepared according totechniques well known in the art of pharmaceutical formulation. As asuspension they may, for example, contain microcrystalline cellulose forimparting bulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweeteners or flavoringagents known in the art. As immediate release tablets, the presentcompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and/or lactose and/or otherexcipients, binders, extenders, disintegrants, diluents and lubricantsknown in the art.

When administered by nasal aerosol or inhalation, the compositions maybe prepared according to techniques well known in the art ofpharmaceutical formulation and may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, and/or other solubilizing ordispersing agents known in the art.

When administered as injectable solutions or suspensions, the presentcompositions may be formulated according to techniques well known in thepharmaceutical art, using suitable non-toxic, parenterally acceptablediluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer'ssolution, an isotonic sodium chloride solution, or other suitabledispersing or wetting and suspending agents, including synthetic mono-or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, thesecompositions may be prepared by techniques well known in thepharmaceutical art by mixing the drug with a-suitable non-irritatingexcipient, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures, butliquify and/or dissolve in the rectal cavity to release the drug.

The pharmaceutical compositions of the present invention may contain anamount of the inventive compound(s) effective for the inhibition ofretroviral replication, and preferably an amount effective for thetreatment and/or prevention of infection by HIV. The effective amount ofa compound of the present invention may be determined by one of ordinaryskill in the art, and includes amounts such as those from about 1 to 150mg/kg of body weight of active compound per day. It will be understoodthat the specific dose level and frequency of dosage for any particularsubject may be varied and will depend upon a variety of factorsincluding the activity of the specific compound employed, the metabolicstability and length of action of that compound, the species, age, bodyweight, general health, sex and diet of the subject, the mode and timeof administration, rate of excretion, drug combination, and severity ofthe particular condition.

Viral hosts which are preferred subjects for treatment and/or preventionof retroviral infections include animals, most preferably mammalianspecies such as humans, and domestic animals such as dogs, cats and thelike. A dose for adult humans is preferably between about 10 and about50 mg/kg of body weight per day, which may be administered in a singledose or in the form of individual divided doses, such as from 1-4 timesper day.

The compounds of the present invention may be employed alone or incombination with other suitable therapeutic agents useful in thetreatment of retroviral infections such as AIDS, such as other antiviralagents, immunomodulators, antibiotics or vaccines.

Other therapeutic agents may include, but are not restricted to thefollowing: antivirals exemplified by AL-721, interferon beta,polymannoacetate, ganciclovir, DDC (dideoxycytidine), d4T, DDI(dideoxyinosine), Foscarnet (trisodium phosphonoformate), HPA-23,eflornithine, Peptide T (octapeptide sequence), Reticulose(nucleophosphoprotein), AZT, ansamycin LM 427, trimetrexate, UA-001,ribavirin, α-interferon, acyclovir, 3TC, PMEA, nevirapine, pyridinones(e.g. L-697,661), BHAPs (e.g. U-90152), alpha-APA derivatives (e.g. R18893), TIBO derivatives (e.g. R 82913), and Ro 31-8959;immunomodulators exemplified by bropirimine, Ampligen (mismatched RNA),Anti-human alpha interferon antibody, Colony Stimulating Factor(GM-CSF), CL246,738, IMREG-1, IMREG-2, diethyl dithio carbamate,interleukin-2, inosine pranobex, methionine enkephalin, MTP-PE(muramyl-tripeptide), Thymypentin (TP-5) (thymic compound), recombinanterythoropoietin, naltrexone, TNF (tumor necrosis factor); andantibiotics exemplified by Pentam 300 (pentamidine isethionate).

In particular, the HIV protease inhibitors of the present invention maybe used in combination with other anti-retroviral therapies for thetreatment of AIDS. Such combined therapies may include, but are notlimited to, a compound of the present invention in combination with:other (e.g., those other than inhibitors of the present invention) HIVprotease inhibitors (e.g. Ro 31-8959); nucleoside and non-nucleosidereverse transcriptase inhibitor(s), preferably nucleoside reversetranscriptase inhibitors such as AZT, DDI, d4T, DDC, 3TC or PMEA, andnon-nucleoside reverse transcriptase inhibitors such as nevirapine,pyridinones (e.g. L-697,661), BHAPs (e.g. U-90152), alpha-APAderivatives (e.g., R 18893), and TIBO derivatives (e.g. R 82913);inhibitor(s) of tat such as RO24-7429; drug(s) which inhibit binding ofthe virus to CD₄ receptors; inhibitor(s) of RNase, integrase, or rev;and immunomodulator(s) such as IFN-α (α-interferon).

The above compounds to be employed in combination with the compounds ofthe present invention will be used, for example, in amounts as indicatedin the Physicians' Desk Reference (PDR) or as otherwise determined byone of ordinary skill in the art. The aforementioned combined therapiesmay, for example, be conducted simultaneously or sequentially.

The instant invention also provides methods for the inhibition ofretroviral proteases by contacting said protease with a compound of thepresent invention capable of said inhibition, and particularly for thetreatment and/or prevention of retroviral infections. Treatment and/orprevention of infection by the human imunodeficiency viruses ispreferred. The methods of the present invention preferably comprise thestep of administering to a subject in need thereof one or more of thepresent compounds capable of treatment and/or prevention of retroviralinfection in an amount effective therefor. Other therapeutic agents suchas those described above may be employed with the inventive compounds inthe present methods.

The compounds of the present invention are also useful in thepreparation of other compounds of the formula I. Thus, for example, onecompound of the present invention may be employed in the preparation ofanother compound of the present invention, where the latter compound hasgreater potency against the same or a different retrovirus than theformer.

The following Examples will serve to illustrate the preparation ofcompounds of the present invention, and are not intended to limit thescope or spirit of the instant claims. The following abbreviations areemployed in the Examples:

Abbreviations

Ph=phenyl

Bn=benzyl

t-Bu=tertiary-butyl

Me=methyl

Et=ethyl

Ts=tosyl (p-toluenesulfonyl)

Bz=benzoyl

Phe=phenylalanine

Val=valine

TMS=trimethylsilyl

TBS or TBDMS=tert-butyldimethylsilyl

FMOC=fluorenylmethoxycarbonyl

Teoc=trimethylsilylethoxycarbonyl

Boc=tert-butoxycarbonyl

Cbz or Z=carbobenzoxy (or carbobenzyloxy or benzyloxycarbonyl)

THF=tetrahydrofuran

Et₂ O=diethylether

EtOAc=ethyl acetate

DMF=dimethylformamide

MeOH=methanol

EtOH=ethanol

i-PrOH=iso-propanol

t-BuOH=tert-butanol

DMSO=dimethylsulfoxide

DME=1,2-dimethoxyethane

HMPA=hexamethylphosphoric triamide

HOAc or AcOH=acetic acid

TFA=trifluoroacetic acid

i-Pr₂ NEt=diisopropylethylamine

Et₃ N=triethylamine

DMAP=4-dimethylaminopyridine

MeLi=methyl lithium

n-BuLi=n-butyllithium

s-BuLi=sec-butyllithium

n-Bu₄ NF·nH₂ O=tetra-n-butylammonium fluoride hydrate

n-Bu₄ NBr=tetra-n-butylammonium bromide

n-Bu₄ NI=tetra-n-bunylammonium iodide

EDC (or EDC·HCl) or EDCI (orEDCI·HCl)=3-ethyl-3'-(dimethylamino)propylcarbodiimide hydrochloride (or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)

HOBT or HOBT·H₂ O=1-hydroxybenzotriazole hydrate

KN(TMS)₂ =potassium bis (trimethylsilyl)amide

NaN (TMS)₂ =sodium bis (trimethylsilyl)amide

Boc-ON=[2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile]

AcCl=acetyl chloride

BOP-C1=Bis(2-oxo-3-oxazolidinyl)phosphinic chloride

BOP reagent=benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate

PPh₃ =triphenylphosphine

DEAD=diethylazodicarboxylate

Me₂ S=dimethylsulfide

Ti(i-Pro)₄ =titanium(IV) isopropoxide

KOAc=potassium acetate

Dibal or DIBAL-H=diisobutylaluminum hydride

Cbz-C1=carbobenzoxy chloride (benzyl chloroformate)

PMA=phosphomolybdic acid

min=minute(s)

h or hr=hour(s)

L=liter

ml or mL=milliliter

μl or μL=microliter

g=gram(s)

mg=milligram(s)

mol=mole(s)

mmol=millimole(s)

RT=room temperature

sat. or sat'd.=saturated

aq.=aqueous

TLC=thin layer chromatography

HPLC=high performance liquid chromatography

UV=ultraviolet

MS or Mass Spec.=mass spectrometry

NMR=nuclear magnetic resonance

mp=melting point

hex=hexane

Tf=triflate

NaHB(OAc)₃ =sodium triacetoxyborohydride

p-TsOH=p-toluenesulfonic acid

m-CPBA=metachloroperbenzoic acid

DCC=dicyclohexylcarbodiimide

NBS=N-bromosuccinimide

PPTs=Pyridinium p-tosylate

PCC=pyridinium chlorochromate

BF₃ ·Et₂ O=boron trifluoride etherate

Compounds in the following Examples are referred to by the step andnumber of the Example in which they are prepared. For example, "Compound1c" denotes the compound prepared in step (c) of Example 1; "Compound39" denotes the compound prepared in Example 39, which Example containsa single step.

EXAMPLE 1

Preparation of [1S-[1R*, 2S* (2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl](phenylmethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 1c)

(a) Compound 1a(iv) ##STR49##

(i) Diazomethane-Et₂ O solution

To the mixture of 40% aqueous KOH (75 ml) and Et₂ O (255 ml) cooled at0° C. was added 1-methyl-3-nitro-1-nitrosoguanidine (23.85 g, 162.2mmol) portionwise. The mixture was swirled several times during eachaddition. After 10 min, the resulting yellow Et₂ O layer was decantedover KOH pellets at 0° C. and dried for 2.0 h at 0° C.

(ii) Compound 1a(ii) ##STR50##

To the solution of N-Boc-L-phenylalanine (14.34 g, 54.05 mmol) in dryTHF (80 ml) cooled at -20° C. to -25° C. (dry ice-CCl₄ bath) was addedisobutyl chloroformate (7.01 ml, 54.05 mmol) over 5 min, followed by4-methylmorpholine (5.94 ml, 54.05 mmol) and the mixture was stirred for20 min. The white precipitate was removed by filtration under argonatmosphere and washed with ca. 70 ml of dry THF. The combined THFsolution of mixed anhydride was cooled to -5° C. and poured into theabove prepared diazomethane in Et20 solution at 0° C. The resultingyellow solution was kept at 0° C. for 2.0 h, then RT overnight. N₂ wasthen bubbled through the light-yellow solution for 30 min, and Et₂ O(400 ml) then added. The solution was washed with H₂ O (400 ml),saturated NaHCO₃ (300.ml) and brine (300 ml), and was dried overanhydrous MgSO₄. Concentration in vacuo afforded a yellow residue, whichwas triturated with hexane to give, after drying over P₂ O₅ overnightunder high vacuum, 14.72 g (94%) of the title α-diazoketone as a paleyellow solid. This material was used immediately in the reaction of thenext step without further purification.

(iii) Compound 1a (iii) ##STR51##

To the solution of the crude α-diazoketone prepared above (14.72 g,50.87 mmol) in dry Et₂ O (500 ml) cooled at 0° C. was added, dropwise, asolution of 4N HCl in dioxane (12.72 ml, 50.87 mmol) while maintainingthe temperature below 5° C. The reaction mixture was then stirred at 0°C. for 1.0 h. TLC (hexane-EtOAc 4:1) showed trace amounts of thestarting α-diazoketone remained. Additional 4N HCl in dioxane (636 μl,0.05 eq., 2.54 mmol) was added and the mixture was stirred at 0° C. forone additional hour.

Concentration in vacuo gave a residue which was dissolved in hot Et₂ O(60 ml). Hexane (200 ml) was slowly added and the mixture allowed tostand for 2.0 h at 5° C. The solid was filtered and dried over P₂ O₅under high vacuum to afford 9.58 g (first crop) of the titleα-chloroketone. The filtrate was concentrated to dryness and the residuewas again recrystallized from Et₂ O-hexane to give an additional 4.41 g(second crop) of the above α-chloroketone. Total yield: 13.99 g (92%).

(iv) Compound 1a(iv)

NaBH₄ (1.59 g; 42 mmol) was added to a solution of the α-chloroketoneprepared above (5 g; 16.8 mmol) in 84 ml of THF and 9 ml of H₂ O at 0°C. After stirring at 0° C. for 45 min the reaction mixture wasconcentrated to dryness. The residue was stirred at 0° C. with EtOAc(150 ml) and H₂ O (25 ml) while saturated KHSO3 solution was carefullyadded until the pH was ˜1.5. This mixture was then diluted with 350 mlof EtOAc and the layers were separated. The organic layer was washedwith H₂ O (100 ml) and brine (100 ml). After drying over MgSO₄, theorganic layer was concentrated to a white solid. A portion of this solid(4.89 g) was recrystallized from 70 ml of hot EtOAc to afford 2.47 g(50%) of Compound la(iv) as a white solid containing a few percent ofits diastereomer, the following Compound 1a(v): ##STR52## (b) Compound1b(i) ##STR53##

0.71M KOH in EtOH (14.7 ml; 10.4 mmol) was added to a suspension ofCompound 1a(iv) (2.6 g; 8.67 mmol) in 87 ml of EtOH at RT. The reactionwas stirred 1.5 h at RT, during which time the thick suspension became afine powdery one. At this time, the EtOH was removed in vacuo and theresidue was partitioned between EtOAc (200 ml) and H₂ O (200 ml). Theorganic layer was washed with saturated NH₄ Cl solution (2×100 ml), H₂ O(2×100 ml), and brine (100 ml). After drying over MgSO₄, the EtOAc wasremoved in vacuo and the solid white residue was recrystallized bydissolving in 10 ml of refluxing EtOAc and adding 190 ml of hexane. Theresulting crystalline suspension was allowed to cool to -40° C. andstand overnight. Filtration, rinsing with hexane, and drying under highvacuum for two hours afforded 1.92 g (84%) of Compound 1b(i) as acolorless crystalline solid. This material was 99.1% diastereomericallypure by HPLC.

Compound 1b(ii) ##STR54##

The diastereomeric epoxide 1b(ii) is prepared by a procedure analogousto the one used for 1b(i) starting from the minor diastereomericchlorohydrin isolated by column chromatography from 1a(iv) above.

Alternatively, to a solution of the compound: ##STR55## (forpreparation, see Luly et al., J. Org. Chem., 52, 1487-1492 (1987)) indioxane at 0° C. was added a suspension of NBS in H₂ O. After 5 min, thereaction mixture was warmed to RT and stirred for 2.0 h. The reactionmixture was then diluted with MeOH and K₂ CO₃ was added. After 3.0 h,the volatiles were removed in vacuo and the residue was partitionedbetween CH₂ Cl₂ and H₂ O. The organic layer was concentrated in vacuo togive a mixture of Compounds 1b(i) and 1b(ii) (3:1 mixture, 1b(i):1b(ii)) as a colorless solid.

(c) Compound 1c ##STR56##

A DMF (2.5 mL) solution of Compound 1b(i) (1.97 g, 7.48 mmol) and benzylamine (0.41 mL, 3.74 mmol) was heated under argon for 7 h at 105°-108°C., then stirred overnight at RT. After heating an additional 1.5 h at105°-108° C., the volatiles were evaporated in vacuo. The resultingresidue was co-evaporated twice with MeOH/CH₂ Cl₂ and purified by flashcolumn chromatography (silica gel, 5 by 19 cm) , eluting with 0.5,1,2,3,4,7, and then 10% MeOH:CH₂ Cl₂ to give Compound 1c (1.39 g, yield)as a colorless solid. Anal. Calc. for C₃₇ H₅₁ N₃ O₅ ·1.63 H₂ O:

C, 68.68; H, 8.45; N, 6.49 Found: C, 68.35; H, 8.10; N, 6.82

EXAMPLE 2

Preparation of [1S-[1R*, 2S* (2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 2) ##STR57##

To an EtOH (5 mL) solution of Compound 1c (90 mg, 0.142 mmol) and.cyclohexene (2.5 mL) at RT was added Pd(OH)₂ (41 mg, 20% on carbon). Thereaction mixture was refluxed at 90° C. for 1 h, filtered hot throughCelite, and the volatiles were removed in vacuo to leave a colorlesssolid (74 mg). The residue was purified by flash chromatography (silicagel, 1 by 12.5 cm), eluting with 0.5, 2, 4, 8, and then 9% MeOH:CH₂ Cl₂to give the title Compound 2 (53 mg, 69% yield) as a colorless solid.m.p. 178°-179.5° C.; [α]_(D) =-7.07° (c 0.1, MeOH ) . MS: 544 (M+H).Anal. Calc. for C₃₀ H₄₅ N₃ O₆ ·0.8 H₂ O:

C, 64.57; H, 8.42; N, 7.53 Found: C, 64.53; H, 8.30; N, 7.57

EXAMPLE 3

Preparation of [1S-[1R*, 2R*(2R*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 3) ##STR58##

Compound 1b(ii) was converted to the title Compound 3 by proceduresanalogous to those described for Compounds 1c and 2. m.p. 140°-141° C.;[α]D²⁵ =-42.38° (c 0.29, MeOH). MS: 544 (M+H). Anal. Calc. for C₃₀ H₄₅N₃ O₆ ·1.45 H₂ O:

C, 63.24; H, 8.47; N, 7.37 Found: C, 63.25; H, 8.36; N, 7.36

EXAMPLE 4

Preparation of [1S-[1R*, 2S*(2R*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl](phenylmethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 4b)

(a) Compound 4a ##STR59##

A DMF (0.4 mL) solution of Compound 1b(i) (75 mg, 0.285 mmol) and benzylamine (0.025 mL, 0.229 mmol) was heated for 18 h at 85° C. and thevolatiles were evaporated in vacuo at 30° C. The solid residue (100 mg)was purified by flash column chromatography (silica gel, 1.5 by 11 cm),eluting with 0.5, 4, and then 8% MeOH:CH₂ Cl₂ to give Compound 4a (50mg, 41% yield) as a colorless solid.

(b) Compound 4b ##STR60##

A DMF (0.3 mL) solution of Compound 4a (48 mg, 0.11 mmol) and Compound1b(ii) (55 mg, 0.21 mmol) was heated for 7 h at 105-°110° C., thenstored at -40° C. overnight. After warming to RT, the volatiles wereevaporated in vacuo at 30° C. The oily-solid residue (120 mg) waspurified by flash column chromatography (silica gel, 1 by 16 cm),eluting with 0.5, 1, 1.5, and then 2% MeOH:CH₂ Cl₂ to give Compound 4b(74 mg, ˜100% yield) as a colorless solid. R_(f) =0.69 (7% MeOH:CH₂Cl₂).

EXAMPLE 5

Preparation of[1S-[1R*,2S*(2R*,3R*)]][3-[[3-[[(1,1-Dimethylethoxy)carbonyl[amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 5) ##STR61##

Compound 4b was deprotected using a procedure analogous to that forCompound 2 to give the title Compound 5. m.p. 151°-153° C.; [α]_(D) ²⁵=-22.93° (c 0.23, MeOH). MS: 544 (M+H). Anal. Calc. for C₃₀ H₄₅ N₃ O₆·0.67 H₂ O:

C, 64.83; H, 8.40; N, 7.56 Found: C, 64.84; H, 8.37; N, 7.55

EXAMPLE 6

Preparation of(2S)-2,2'-[(Phenylmethyl)imino-bis[1-hydroxy-2,1-ethanediyl]bis-1-pyrrolidine-carboxylicacid], bis(1,1-dimethylether) ester, single isomer (A) (Compound 6b)

(a) Compounds 6a(i) and 6a(ii) ##STR62## Compound 6a(i) faster movingisomer Compound 6a(ii) slower moving isomer

Compounds 6a (i) and 6a (ii) (unknown stereochemistry) were prepared bya procedure analogous to the synthesis of Compounds 1b(i) and 1b(ii) inwhich Boc-(L)-proline was employed in place of N-Boc-L-phenylalanine.

(b) Compound 6b ##STR63##

Compound 6a(ii) was converted to the title Compound 6b by opening withbenzyl amine and then reacting with another molecule of 6a(ii) analogousto the two-step procedure used for the preparation of Compound 4b. R_(f)=0.36 (3:1 EtOAc/hexane) (oil).

EXAMPLE 7

Preparation of(2S)-2,2'-[Iminobis(1-hydroxy-2,1-ethanediyl]bis-(1-pyrrolidinecarboxylicacid), bis(1,1-dimethylether)ester, single isomer (A) (Compound 7)##STR64##

A suspension of 0.069 g (0.13 mmol) of Compound 6b and 10 mg of Pd(OH)2in 1.5 ml of MeOH was stirred under a H₂ atmosphere (balloon) at RTovernight. The mixture was filtered through a micropore fritted funnel(MeOH wash) and evaporated. The crude product was purified by flashchromatography (20 mm×6"; 10% MeOH/CH₂ Cl₂ +1% NH₄ OH) to give 41 mg(<72%) of slightly impure material. This material was combined with 41mg of material from a previous reaction and recrystallized fromEtOAc/Hexane to give 32 mg of the title Compound 7 as a white solid.m.p.=181°-184° C.; [α]_(D) ²⁵ =-86° (c 0.1, MeOH). MS: 444 (M+H). Anal.Calc. for C₂₂ H₄₁ N₃ O₆ ·0.52 H₂ O:

C, 58.34; H, 9.35; N, 9.28; Found: C, 58.39; H, 9.44; N, 9.23.

EXAMPLE 8

Preparation of[S-(R*,R*)]-2-[2-[[[S-(R*,S*)]-1-[1-[(1,1-Dimethylethoxy)carbonyl]-pyrrolidinyl],2-hydroxyethyl]amino]-hydroxyethyl]-1-pyrrolidine-carboxylic acid,(1,1-dimethylethyl) ester (Compound 8) ##STR65##

Compounds 6a(i) and 6a(ii) were converted to the title Compound 8 (whitesolid) by procedures analogous to those used for the synthesis ofCompound 7 except that epoxide 6a(ii) was opened with 2 equivalents ofbenzyl amine and the resulting product was reacted with epoxide 6a(i) bya procedure analogous to that used for Compound 4b. m.p. 44°-48° C.;[α]_(D) =-67.3° (c 0.26, CHCl₃) Mass Spec. 444 (M+H) Anal. Calc. for C₂₂H₄₁ N₃ O₆ ·0.56 H₂ O:

C, 58.24; H, 9.36; N, 9.26 Found: C, 58.50; H, 9.63; N, 9.00

EXAMPLE 9

Preparation of [S-(R*,R*)]-3,3-[[(Phenylmethyl)imino]bis(1-hydroxy-2,1-ethanediyl)]bis[2(1H)-isoquinolinecarboxylicacid, bis(1,1-dimethylethyl) ester (Compound 9b)

(a) Compound 9a(i) ##STR66## and

Compound 9a(ii) ##STR67##

Compounds 9a(i) (major) and 9a(ii) (minor) were prepared by a procedureanalogous to the synthesis of Compounds 1b(i) and 1b(ii) in whichBoc-(L)-tetrahydroisoquinoline-2-carboxylic acid (see J. Am. Chem. Soc.,70, 180 (1948); ibid 84, 4487 (1962)) was employed in place ofN-Boc-L-phenylalanine.

(b) Compound 9b ##STR68##

Compound 9a(i) was converted to the title Compound 9b (light-yellow oil)by opening with 2 equivalents of benzyl amine and then reacting withanother molecule of 9a(i) analogous to the two-step procedure used forthe preparation of Compound 4b.

¹ H NMR (CD₃ OD): δ1.43-1.46 (brs's, 18H), 2.45 (m, 4H), 2.61 (m, 2H),2.87 (m, 2H), 3.43 (m, 1H), 3.55 (m, 3H), 4.22 (m, 4H), 4.71 (m, 2H),7.00-7.25 (m, 13H).

EXAMPLE 10

Preparation of[S-(R*,R*)]-3,3'-[Iminobis(1-hydroxy-2,1-ethanediyl)]-bis[2(1H)-isoquinolinecarboxylicacid], bis(1,1-dimethylethyl) ester (Compound 10) ##STR69##

Compound 9b was deprotected by a procedure analogous to that used forCompound 7 to give the title Compound 10 (white solid). mp 70°-76° C.;[α]_(D) +33.6° (c 0.25, MeOH); Mass Spec: 568 (M+H) Analysis calc. forC₃₂ H₄₅ N₃ O₆ ·0.69H₂ O:

C, 66.25; H, 8.06; N, 7.24; Found: C, 66.45; H, 7.96; N, 7.04.

EXAMPLE 11

Preparation of [R-(R*,R*)]-3,3'[Iminobis(1-hydroxy-2,1-ethanediyl)]-bis[2(1H)-isoquinolinecarboxylicacid], bis(1,1-dimethyethyl) ester (Compound 11) ##STR70##

Compound 11 (white solid) was prepared from Compound 9a(ii) byprocedures analogous to those used for the synthesis of Compound 10. mp68°-76° C.; [α]_(D) =+34.0° (c 0.05, MeOH). Mass Spec.: 568 (M+H)Analysis calc. for C₃₂ H₄₅ N₃ O₆ ·0.91H₂ O:

C, 65.81; H, 8.08; N, 7.19; Found: C, 65.96; H, 8.15; N, 7.04.

EXAMPLE 12

Preparation of[S-(R*,R*)]-3-[2-[[[S-(R*,S*)]-2-[2-[(1,1-Dimethylethoxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]-2-hydroxyethyl]amino]-1-hydroxyethyl]-3,4-dihydro-2(1H)-isoquino-linecarboxylicacid, (1,1-dimethylethyl) ester (Compound 12) ##STR71##

Compounds 9a(i) and 9a(ii) were converted to the title Compound 12(white solid) by procedures analogous to those used for the synthesis ofCompound 10 except that epoxide 9a(i) was opened with benzyl amine andthe resulting product was reacted with epoxide 9a(ii) by a procedureanalogous to that used for Compound 4b. mp 65°-72 ° C.; [α]_(D) =+20.5°(c 0.19, MeOH). Mass Spec.: 568 (M+H) Analysis calc. for C₃₂ H₄₅ N₃ O₆19 1.13H₂ O:

C, 65.35; H, 8.10; N, 7.15; Found: C, 65.68; N, 7.94; N, 6.82.

EXAMPLE 13

Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(1-methylpropyl)-3,1-propanediyl]]bis-carbamicacid, 1,1 -dimethylethyl ester (Compound 13) ##STR72##

Starting from N-Boc-L-isoleucine in place of N-Boc-L-phenylalanine, thetitle Compound 13 (colorless oil) was prepared using proceduresanalogous to those described for Compounds 1b(i), 4b, and 7. TLC,Rf=0.10, CH₂ Cl₂ :MeOH:NH₄ OH, 95.5:4.9:0.1, (PMA). ¹³ C NMR (CD₃ OD):812.1, 16.7, 24.1, 28.8, 36.1, 52.8, 59.6, 69.6, 80.1, 158.9. Mass Spec.(M+H)⁺ @476

EXAMPLE 14

Preparation of[R-(R*,S*)]-[Iminobis[-1(Cyclohexyl-methyl)-2-hydroxy-3,1-propanediyl]]-biscarbamicacid, bis(1,1dimethylethyl) ester (Compound 14) ##STR73##

Starting from N-Boc-L-cyclohexylalanine in place ofN-Boc-L-phenylalanine, the title Compound 14 (white solid) was preparedusing procedures analogous to those described for Compounds 1b(i), 4b,and 7. [α]_(D) =-33.7° (c 0.18, MeOH). ¹³ C NMR (CDCl₃): δ26.1, 26.4,26.5, 28.4, 32.3, 34.2, 34.3, 38.1, 51.0, 51.6, 72.7, 79.5, 156.4. MassSpec. (M+H )⁺ @556. High Resolution FAB; exact mass calcd. for C₃₀ H₅₈O₆ N₃ (M+H)⁺, 556,4325; Found 556.4304.

EXAMPLE 15

Preparation of[1S-[1R*,2S*(2S*,3R*)1]-[3-[[4-Cyclohexyl-3-[[(1,1-dimethylethoxy)carbonyl]-amino]-2-hydroxybutyl]amino-2-hydroxy-1(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 15) ##STR74##

Compound 4a and the epoxide prepared in Example 14 (i.e., in the stepanalogous to that for Compound 1b(i)) were converted to the titleCompound 15 by procedures analogous to those used for Compounds 4b and7. mp 120°-125° C.; [α]_(D) =-15.0° (c 0.10, MeOH). Mass Spec. (M+H)⁺@550. Analysis calc. for C₃₀ H₅₁ N₃ O₆ ·0.32H₂ O:

C, 64.99; H, 9.20; N, 7.58; Found: C, 65.08; H, 9.46; N, 7.49.

EXAMPLE 16

Preparation of [2S-[2R*,1S*(2S*,3R*)]]-[1-Hydroxy-3-[[(1,1-dimethylethoxy)carbonylamino]-2-hydroxy-4-phenylbutyl]amino]ethyl-2-methylbutyl]carbamicacid, phenylmethyl ester (Compound 16c)

(a) Compound 16a ##STR75##

Compound 16a was prepared by procedures analogous to those used for thesynthesis of Compound 1b(i) in which N-Cbz-L-isoleucine was employed inplace of N-Boc-L-phenylalanine.

(b) Compound 16b ##STR76##

Compound 1b(i) (15.0 g; 56.96 mmol) dissolved in 350 ml of EtOH wasadded, with stirring, over 1 h to 350 ml of concentrated NH₄ OH at 0° C.NH₃ gas was bubbled through the reaction mixture during the addition andfor 1 h after. The reaction was then warmed to RT and stirred overnight.The resulting slurry was diluted with 800 ml EtOAc and the organic layerwashed repeatedly with brine. The organic extracts were dried (MgSO₄)and concentrated to give a white solid which was triturated with 10%i-PrOH/EtOAc to give 4.37 g of Compound 16b. The mother liquors wereevaporated and triturated again as above to give an additional 5.73 g ofCompound 16b (total yield: 10.1 g; 63%).

(c) Compound 16c ##STR77##

Compounds 16a and 16b were reacted by a procedure analogous to that usedfor the preparation of Compound 4b to give the title Compound 16c. mp155°-157° C.; [α]_(D) =+1.3 6° (c 0.22, MeOH). Mass Spec. (M+H)⁺ @544.Analysis calc. for C₃₀ H₄₅ N₃ O₆ ·0.38H₂ O

C, 65.46 H, 8.38 N, 7.63 Found: C, 65.48 H, 8.29 N, 7.61

EXAMPLE 17

Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3- [[3-[[(1,1Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[[4-(phenylmethoxy)phenyl]methyl]propyl]carbamicacid, phenylmethyl ester (Compound 17b)

(a) Compound 17a ##STR78##

Compound 17a was prepared by procedures analogous to those used for thesynthesis of Compound 1b(i) where N-Cbz-O-benzyl-L-tyrosine was employedin place of N-Boc-L-phenylalanine.

(b) Compound 17b ##STR79##

Compounds 17a and 16b were reacted by a procedure analogous to that usedfor the preparation of Compound 4b to give the title Compound 17b. m.p.:154°-155.5° C. [α]_(D) =-19.09° (c 0.24, DMSO). MS (FAB): 684⁺ (M+H)⁺.Anal. Calc. for C₄₀ H₄₉ N₃ O₇ ·0.87H₂ O: C, 68.68; H, 7.31; N, 6.01.Found: C, 68.84; H, 7.18; N, 5.85.

EXAMPLE 18

Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino]-2-hydroxy-1-[[4-(phenylmethoxy)phenyl]methylpropyl]carbamic acid, phenylmethyl ester(Compound 18) ##STR80##

To the mixture of Compound 17b (342 mg, 0.5 retool) and i-Pr₂ NEt (140μl, 0.8 retool) in dry DMF (3.8 ml) cooled at 0° C. was added2-trimethylsilylethyl chloroformate (125 μl, 0.55 retool). The mixturewas stirred at 0° C. for 1.0 hr and diluted with EtOAc (70 ml). H₂ O (50ml) was added and the mixture was extracted with additional EtOAc (2×20ml). The combined organic layers were washed with saturated NaHCO₃ (40ml) and brine (40 ml) and dried over anhydrous Na₂ SO₄. Concentration invacuo followed by flash chromatography (100% CHCl₃ to 2:1 CHCl₃ -EtOAc)afforded 401 mg (97%) of Compound 18 as a white foam. ¹ H-NMR (400 MHz,CDCl₃): 7.17-7.44 (m, 15H), 7.08 (d, J=8.12, 2H), 6.85 (d, J=8.12, 2H),4.99 (s, 2H), 4.58 and 4.72 (bs, 2H), 4.14 (t, J=8.77, 2), 3.70-4.00 (m,4H), 3.15-3.55 (m, 4H), 2.70-3.00 (m, 4H), 1.32 (s, 9H), 0.94 (m, 2H),0.00 (s, 9H).

EXAMPLE 19

Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-Amino-2-hydroxy-4-(4-hydroxyphenyl)butyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethyl-ethyl ester (Compound 19) ##STR81##

To the solution of Compound 18 (401 mg, 0.485 mmol) in 17 ml of 100%EtOH was added 200 mg of Pd(OH)₂. The mixture was stirred under a H₂atmosphere overnight (>16 hrs). The catalyst was removed by filtrationthrough a small plug of Celite and washed several times with MeOH.Concentration in vacuo afforded an oily residue, which afterrecrystallization from CHCl₃ (2.0 ml) and hexane (25 ml) gave 272 mg(93%) of Compound 19 as an off-white solid. This material wasimmediately used in the next Example.

EXAMPLE 20

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(4-hydroxyphenyl)butyl][[2-(trimethylsilyl)-ethoxy]carbonyl]amino]-2-hydroxy-1-(phenylmethylpropyl]carbamicacid, 1,1 -dimethylethyl ester (Compound 20) ##STR82##

To the solution of Compound 19 (121 mg, 0.20 mmol) in 1,4 -dioxane-water(1: 1, 0.6 ml ) was added Et₃ N (42 μl, 0.30 mmol), followed by Boc-ON(59 mg, 0.24 mmol). The mixture was stirred at RT overnight. Thereaction mixture was diluted with EtOAc (25 ml) and washed with H₂ O(2×10 ml). The aqueous layer was extracted with EtOAc (2×25 ml). Thecombined organic layers were washed with saturated NaHCO₃ (20 ml) andbrine (20 ml) and dried over anhydrous Na₂ SO₄. Concentration in vacuofollowed by flash chromatography (100% CHCl₃ to 95:5 CHCl₃ -MeOH) on asilica gel column (190×20 mm) afforded 132 mg of Compound 20 as a glassysolid, which was triturated with hexane to give 126 mg (94%) of Compound20 as a white solid. MS (FAB): 704⁺ (M+H)⁺.

EXAMPLE 21

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-3-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(4-hydroxyphenyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 21) ##STR83##

The mixture of Compound 20 (124 mg, 0.176 mmol) and solid n-Bu₄ NF·nH₂ O(138 mg, 0.529 mmol) in dry THF (0.75 ml) was heated at 50° C. for 4.0hrs. After cooling to room temperature, Celite (1.0 g) was added and thesolvent was removed under reduced pressure. Flash chromatography (100%CHCl₃ to CHCl₃ -MeOH-NH₄ OH: 92:8:0.8) on silica gel column (20×200 mm)afforded 79 mg (81%) of Compound 21 as a white solid. m.p.:151.0°-152.5° C. [α]_(D) =-1.53° (c 0.196, CHCl₃). MS (FAB): 560⁺(M+H)⁺. Anal. Calc. for C₃₀ H₄₅ N₃ O₇ ·0.70H₂ O: C, 62.96; H, 8.17; N,7.34. Found: C, 63.03; H, 8.08; N, 7.27.

EXAMPLE 22

Preparation of [1S-[1R*,2S*(2S,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[(1H-indol-3-yl)methyl]propyl]carbamicacid, phenylmethyl ester (Compound 22b)

(a) Compound 22a ##STR84##

Compound 22a was prepared by procedures analogous to those used for thesynthesis of Compound 1(i) in which N-Cbz-L-tryptophan was employed inplace of N-Boc-L-phenylalanine.

(b) Compound 22b ##STR85##

Compounds 22a and 16b were reacted by a procedure analogous to that usedfor the preparation of Compound 4b to give the title Compound 22b (whitesolid). Elemental Analysis (%) C₃₅ H₄₄ N₄ O₆ ·0.89 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              67.62  67.53                                                   H              7.22   7.14                                                    N              9.01   9.10                                                    ______________________________________                                         m.p. 170°-171° C. [α].sub.D =21.1° (c 0.48,     MeOH)

EXAMPLE 23

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(1H-indol-3-ylmethyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 23) ##STR86##

Compound 22b was converted to the title Compound 23 (white solid) usingprocedures analogous to those for the synthesis of Compounds 18 through21 (di-tert-butyldicarbonate was used instead of BOC-ON to put on theBoc group). Elemental Analysis (%) for C₃₂ H₄₆ N₄ O₆ ·1.09 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              65.24  65.31                                                   H              7.99   8.18                                                    N              9.51   9.44                                                    ______________________________________                                         m.p. 168°-169° C. [α].sub.D =-14.4° (c=0.21,     MeOH)

EXAMPLE 24

Preparation of[1S-[1R*,2S*((2S*,3R*)]]-[3-[[3-[[1,1-Dimethylethoxy)carbonyl]amino-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(2-phenylethyl)propyl]carbamicacid, phenylmethyl ester (Compound 24b)

(a) Compound 24a ##STR87##

Compound 24a was prepared by procedures analogous to those used for thesynthesis of Compound 1b(i), in which N-Cbz-L-homophenylalanine wasemployed in place of N-Boc-L-phenylalanine.

(b) Compound 24b ##STR88##

Compounds 24a and 16b were reacted by a procedure analogous to that usedfor the preparation of Compound 4b to give the title Compound 24b. mp150°-151° C. [α]_(D) =-9.1° (c 0.2, MeOH). Mass Spec. [M+H]⁺ =592.Analysis calc. for C₃₄ H₄₅ N₃ O₆ ·0.43 H₂ O:

C, 68.13; H, 7.71; N, 7.01; Found: C, 68.15; H, 7.58; N, 6.99.

EXAMPLE 25

Preparation of[1S-[1R*,2S*(2S,2R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyll]amino]-2-hydroxy-1-(2-phenylethyl))propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 25) ##STR89##

Compound 24b was converted to the title Compound 25 using proceduresanalogous to those for the synthesis of Compounds 18 through 21. mp145°-148° C.; [α]_(D) =-6° (c 0.3, MeOH). Mass Spec: Fab (M+H)⁺ : 558.Analysis calculated for C₃₁ H₄₇ N₃ O₆ ·0.44H₂ O:

C; 65.82; H; 8.53; N; 7.43; Found: C; 65.69: H; 8.40; N; 7.56.

EXAMPLE 26

Preparation of[1R-[1R*,2R*(2R*,3S*)]]-3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 26b(i)) and

Preparation of [1R-[1R*,2S*(2R*,3S*)]]-3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 26b(ii))

(a) Compound 26a (i) ##STR90## and

Compound 26a(ii) ##STR91##

Compounds 26a(i) and 26a(ii) were prepared by procedures analogous tothose used for the synthesis of Compounds 1b(i) and 1b(ii), in whichN-Boc-D-phenylalanine was employed in place of N-Boc-L-phenylalanine.

(b) Compound 26b(i) ##STR92## and

Compound 26b(ii) ##STR93##

A mixture of Compounds 26a(i) and 26a(ii) were reacted with Compound 16bby a procedure analogous to that used for the preparation of Compound 4b(except that MeOH at 55° was used in place of DMF) to give, afterseparation by silica gel chromatography the title Compounds 26b(i) and26b(ii).

Compound 26b (i ) m.p. 158°-160° C.; [α]_(D) ²⁵ =+14.9° (c 0.35, MeOH).MS: (CI/NH₃): 544 (M+H). Anal. Calc. for C₃₀ H₄₅ N₃ O₆ ·0.67 H₂ O

C, 64.84; H, 8.40; N, 7.56 Found: C, 64.66; H, 8.25; N, 7.74

Compound 26b(ii) m.p. 200°-201° C.; [α]_(D) ²⁵ =+6.0° (c 0.1, DMSO). MS:(FAB): 544 (M+H). Anal. Calc. for C₃₀ H₄₅ N₃ O₆ ·0.32 H₂ O

C, 65.58; H, 8.37; N, 7.65 Found: C, 65.44; H, 8.38; N, 7.79

EXAMPLE 27

Preparation of[1S-[1R*,2R*(3S*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamicacid 1,1,dimethylethyl ester (Compound 27b)

(a) Compound 27a ##STR94##

Compound 1b(ii) was converted to Compound 27a by a procedure analogousto the one used for the preparation of Compound 16b.

(b) Compound 27b ##STR95##

A mixture of Compounds 26a(i) and 26a(ii) were reacted with Compound 27aby a procedure analogous to that used for the preparation of Compound 4b(except that MeOH at 55° was used in place of DMF) to give the titleCompound 27b as a mixture of diastereomers. m.p. 156°-159° C.; MS:(CI/NH₃): 544 (M+H). Anal. Calc. for C₃₀ H₄₅ N₃ O₆ ·0.16 H₂ O

C, 65.91; H, 8.36; N, 7.69 Found: C, 65.89; H, 8.34; N, 7.71

EXAMPLE 28

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[[3-(phenylmethoxy)phenyl]methyl]propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 28g)

(a) Compound 28a ##STR96##

SOCl₂ (1.28 ml) was added dropwise to a solution of DL-meta-tyrosine(3.2 g, 17.7 mmol) in 4.4 ml MeOH at -15° C. and the resulting solutionwas stirred at 0° C. for 2 h, and at RT overnight. The reaction mixturewas concentrated in vacuo and the residue was washed with Et₂ O,filtered, and dried in vacuo to yield 3.2 g (94%) of the HCl salt ofmethyl ester Compound 28a.

(b) Compound 28b ##STR97##

Compound 28a (1.54 g, 6.65 mmol) in 70 ml of 0.2N NaHCO₃ was added to a100 ml aqueous solution of Subtilisin (protease type VIII from bacciluslicheniformis, 3.8 mg) and the reaction mixture was stirred slowly at RTfor 40 min. The pH of this solution was maintained at pH 8.0 with theoccasional addition of 1N NaOH. Unreacted methyl ester of D-m-tyrosinewas extracted 5× with 100 ml portions of EtOAc. The aqueous solution wasacidified with 1N HCl to pH 6.0 and concentrated to 5 ml. The resultingsolid was filtered, washed with 1 ml of cold H₂ O and dried to yield0.45 g of Compound 28b. The filtrate was passed through 20 ml of DowexAG50 in H⁺ form, followed by the elution of desired material with 2%pyridine in H₂ O to yield an additional 0.14 g of Compound 28b (total0.59 g, 98%). This crude product was carried on to the next step.

(c) Compound 28c ##STR98##

Compound 28b (0,473 g, 2.61 mmol) was reacted with BOC-anhydride (0.613g, 2.81 mmol) in 20 ml of absolute EtOH overnight at RT. The reactionmixture was concentrated in vacuo, and the residue was dissolved inEtOAc (400 ml) and washed with H₂ O, brine, dried (Na₂ SO₄), filteredand concentrated in vacuo. The crude product was chromatographed through80 g of silica gel using a (2:1:97) MeOH:HOAc:CHCl₃ solvent system. Theresulting product was crystallized from CHCl₃ (15 ml) to yield 0.41 g(59%) of Compound 28c. [α]_(D) =+10.8° (MeOH, c=1.0)

(d) Compound 28d ##STR99##

Compound 28c (0.41 g, 1.46 mmol), benzyl bromide (0.51 g,,2.98 mmol) andCs₂ CO₃ (0.97 g, 2.96 mmol) were stirred in DMF (2.5 ml) overnight. Thereaction mixture was diluted with 200 ml of EtOAc and the organicsolution was washed with water, brine, dried (Na₂ SO₄) and concentratedin vacuo. The product was crystallized from 10 ml of (1:1) Et₂ O:hexaneto yield 0.54 g (81%) of Compound 28d.

(e) Compound 28e ##STR100##

Compound 28d (1.147 g; 2.49 mmol) was dissolved in 2.5 ml of THF and 2.5ml of 1N LiOH and stirred at RT for 20 min. An additional 2.0 ml of THFwas added and the reaction was stirred for 40 more min. The reactionmixture was neutralized with 2.5 ml of 1N HCl at 0° C. and concentratedin vacuo to 4 ml. The product was extracted with EtOAC and this solutionwas washed with brine, dried (Na₂ SO₄), and concentrated in vacuo. Theresidue was redissolved in 50 ml of saturated NaHCO₃ and washed with Et₂O (3×). The bicarbonate solution was neutralized with 1N HCl and theproduct was extracted with EtOAc. The organic extracts were washed withbrine, dried (Na₂ SO₄) and concentrated in vacuo to yield Compound 28e(0.84 g, 91%).

(f) Compound 28f ##STR101##

Compound 28e was converted into Compound 28f by procedures analogous tothose used for the synthesis of Compound 1b(i).

(g) Compound 28g ##STR102##

Compounds 28f and 16b were reacted by a procedure analogous to that usedfor the preparation of Compound 4b to give the title Compound 28g.mp=125°-145° C. High Resolution mass spec: (M+H)⁺ =650.3802;theory=650.3805.

EXAMPLE 29

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino],2-hydroxy-4-(3-hydroxyphenyl)butyl]-amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 29) ##STR103##

The benzyl group of Compound 28 g (0.177 mmol) was removed byhydrogenolysis (MeOH, cat. Pd(OH)₂, H₂) by a procedure analogous to thatused for the preparation of Compound 7 to give, after silica gelchromatography, 53 mg (51%) of the title Compound 29. m.p.=193°-196° C.,[α]_(D) =-5.65° (MeOH, c=0.23) High Resolution mass spec: (M+H)⁺560.3343 theory=560.3336.

EXAMPLE 30

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(4-pyridinylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 30g)

(a) Compound 30a ##STR104##

Boc-L-serine (4.03 g, 19.6 mmol) and benzyl bromide (3.35 g, 19.6 mmol)were stirred with Cs₂ CO₃ (7.5 g, 23.0 mmol) in 20 ml of DMF at 5° C.for 4 h. The reaction was diluted with Et₂ O (500 ml) and the resultingmixture was washed with H₂ O, brine, dried (Na₂ SO₄) and concentrated invacuo. The resulting residue solidified and was triturated with hexane,filtered, and dried in vacuo to yield Compound 30a as a white solid (mp62°-64° C., 5.02 g, 86%).

(b) Compound 30b ##STR105##

Compound 30a (5.0 g, 16.9 mmol) was dissolved in 10 ml of pyridine, andthe reaction was cooled to -10° C. Tosyl chloride (3.24 g, 17.0 mmol)was added portionwise and the reaction mixture was stirred at -10° C.for 4 h. Crushed ice was added to the reaction mixture which was stirreduntil the product solidified. The solid was filtered and washedthoroughly with water and finally dried over P₂ O₅ overnight to giveCompound 30b (mp 88°-90° C., 6.8 g, 80%).

(c) Compound 30c ##STR106##

Compound 30b (5.0 g, 11.12 mmol) was partially dissolved in 26 ml ofacetone. NaI (1.9 g, 12.75 mmol) was added and the reaction mixture wasstirred for 48 h. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The resulting residue was chromatographed on 200g of silica gel using (5:95) acetone:hexane 3.6 g, 82%) to give Compound30c as a white solid (mp 78°-80° C.,

(d) Compound 30d ##STR107##

Three grams of zinc dust and 3 g of copper (II) acetate monohydrate weresuspended in 6 ml of glacial HOAc and this mixture was stirred until itsolidified (15 min). The mixture was triturated with Et₂ O andtransferred to a filter funnel under a stream of argon. The solid waswashed with Et₂ O (200 ml) followed by benzene (50 ml). The resultingZn/Cu couple reagent was dried in vacuo over P₂ O₅ for 2 h; 0.54 g of itwas suspended in 3 ml of benzene and 0.6 ml of dimethylacetamide, andsonicated while a solution of Compound 30c (1.82 g, 4.06 mmol) in 7 mlof benzene was added slowly. The reaction mixture was sonicated for 45min and then diluted with 4 ml of benzene. 4-Bromopyridine (0.64 g, 4.06mmol) and Pd((Ph)₃ P)₂ Cl ₂ (0.23 g) was added and the reaction mixturewas stirred at 40° C. for 1 h. The reaction mixture was diluted withEtOAc (200 ml) and filtered. The filtrate was stirred with 50 ml of 0.1NHCl then neutralized with saturated NaHCO₃. The organic layer wasseparated, washed with H₂ O brine, dried (Na₂ SO₄) and concentrated. Thecrude product was chromatographed on 80 g of silica gel using (2:8)acetone:hexane to give Compound 30d (0.71 g, 49%).

(e) Compound 30e ##STR108##

Compound 30d (1.2 mmol) was saponified with aqueous LiOH (1.3 ml of 1Nsolution) in 1.2 ml THF using a procedure analogous to the one used forCompound 28e to give 0.28 g of the title Compound 30e (m.p.=218° C.).

(f) Compound 30f ##STR109##

Compound 30e was converted into Compound 30f by procedures analogous tothose used for the synthesis of Compound 1b(i).

(g) Compound 30g ##STR110##

Compounds 30f and 16b were reacted by a procedure analogous to that usedfor the preparation of Compound 4b to give the title Compound 30g.

High Resolution mass spec(M+H)⁺ 545.3347⁺ Theoretical (M+H)⁺ 545.3339⁺ ¹H (CD₃ OD, 300 MHz, 50° C.): δ 8.39-8.37 (m, 2H) , 7.31-7.14 (m, 7H),3.76-3.59 (m, 4H), 3.05-3.27 (m, 2H), 2.60-2.85 (m, 6H), 1.29 (br s,9H).

EXAMPLE 31 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino-2-hydroxy-1-(6-quinolinylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 31i)

(a) Compound 31a ##STR111##

6-Methylquinoline (7.0 g, 49 mmol) and selenium oxide (6.0 g, 54 mmol)were heated at 150° C. for 1 h and at 220° C. for 30 min. The reactionmixture was cooled to RT and the residue was triturated with MeOH andfiltered. The filtrate was concentrated in vacuo, and the crude productwas chromatographed on 250 g of silica gel using 3:7 EtOAc:Hexane. Theappropriate fractions were combined and concentrated to yield 3.8 g(49%) of Compound 31a as a white solid. m.p. 93°-95° C.

(b) Compound 31b ##STR112##

Compound 31a (1.65 g, 10.5 mmol) was dissolved in 50 ml of MeOH, cooledto 5° C. and NaBH₄ (0.397g, 10.5 mmol) was added and the reactionmixture was stirred for 15 min. After the addition of 10 ml saturatedNH₄ Cl, the reaction mixture was concentrated to 10 ml and extractedwith EtOAc. The organic layer was washed with H₂ O, brine, dried (Na₂SO₄), and concentrated in vacuo to yield a viscous oil which on standingsolidified (74°-78° C.). This material was dissolved in Et₂ O and 4N HClwas added until acidic. The HCl salt that precipitated was filtered anddried to yield 1.56 g (76%) of Compound 31b as its hydrochloride salt.

(c) Compound 31c ##STR113##

SOCl₂ (4.5 ml) was added to Compound 31b (1.46 g, 7.5 mmol). Thereaction mixture was heated at 110° C. for 1 h, and excess SOCl₂ wasdistilled off. The residue was dissolved in H₂ O and 1N KOH was addeduntil basic (pH 12). The product was extracted with EtOAc and thissolution was washed with H₂ O, brine, dried (Na₂ SO₄) and concentratedto yield Compound 31c (1.22 g, 91%) as a crystalline solid. m.p. 65°-68°C.

(d) Compound 31d ##STR114##

Diethylaminomalonate (4.23 g, 20 mmol), di-tert-butyldicarbonate (4.4 g,20 mmol) and Et₃ N (2.8 ml, 20 mmol) were dissolved and stirred in 150ml of absolute EtOH for 24 h. The reaction mixture was concentrated invacuo and the residue was dissolved in EtOAc (300 ml). This was washedwith aqueous KHSO₄ (10%), brine, dried (Na₂ SO₄), filtered andconcentrated in vacuo to yield Compound 31d (4.3 g, 78%) as an oil.

(e) Compound 31e ##STR115##

Sodium ethoxide (4.27M in EtOH, 3.0 ml, 12.8 mmol) was added to an EtOH(5 ml) solution of Compound 31d (3.52 g, 12.8 mmol), followed by theaddition of Compound 31c (1.13 g, 6.4 mmol). The reaction mixture wasrefluxed for 3.5 h. Celite (2 g) was added and the mixture wasconcentrated and chromatographed on 80 g of Merck silica gel to yieldCompound 31e (2.03 g, 76%) as a crystalline solid. m.p. 110°-113° C.

(f) Compound 31f ##STR116##

Compound 31e (0.8 g, 1.9 mmol) was dissolved in 1 ml of THF and 2.2 mlof 1N LiOH. The reaction mixture was stirred at 40° C. for 4 hr,concentrated down to 2 ml and HOAc was added until pH 4 was reached. Themono-acid precipitated and was filtered. Without further purificationthis material was suspended in dioxane and the reaction mixture washeated at reflux for 2 hr. The reaction was concentrated and theresulting residue was chromatographed on 50 g of Merck silica gel using(3:7) acetone:hexane to afford Compound 31f (0.52 g, 80%). m.p. 92°-95°C.

(g) Compound 31g ##STR117##

Compound 31f (1.8 g, 5.2 mmol) in 45 ml of DMF was added dropwise to 700ml of H₂ O containing 10 mg of Subtlisin protease VII and 50 ml of 0.2NNaHCO₃. After the addition, the pH was maintained at 7.5 to 8.0 with theoccasional addition of 0.1N NaOH. After 2.5 h the solution was extractedwith EtOAc and the aqueous layer was acidified to pH 4 with HOAc. Theaqueous layer was concentrated in vacuo and the crude product waschromatographed on 80 g of Merck silica gel using 16:1.5:0.25 CH₂ Cl₂:MeOH:HOAc to afford Compound 31 g (0.82 g, 90%). m.p. 184°-189° C.(dec) [α]_(D) =+29.0° (c 0.77, MeOH)

(h) Compound 31h ##STR118##

Compound 31h was prepared from Compound 31g by a multi-step procedureanalogous to that used for the conversion of N-Boc-L-phenylalanine toCompound 1b(i). m.p. 136°-140° C.

(i) Compound 31i ##STR119##

Compound 31h (100.9 mg, 0.321 mmol) was reacted with Compound 16b (90mg, 0.321 mmol) by a procedure analogous to that of Example 4b to affordthe title Compound 31i (0.113 g; 59%) as a white solid. m.p. 105°-112°C.; [α]_(D) =+4.55° (C 0.88, MeOH) .

EXAMPLE 32 Preparation of[2R-(2R*,3S*)]-1,1'-(Phenylmethyl)iminobis(3-amino-4-phenyl-2-butanol)hydrochloridesalt (Compound 32) ##STR120##

To neat Compound 1c (117 mg, 0.185 mmol) at 0° C. was added HCl indioxane (2.0 mL, 4M). The reaction mixture was stirred at 0° C. for 15min and then 1.15 h at RT. The volatiles were then removed in vacuo andthe residue co-evaporated with dry Et₂ O. The resulting solid was driedunder high vacuum (P₂ O₅) for 4 h to give the title Compound 32 as acolorless solid (91 mg), which was used without further purification asthe tri-HCl salt. R_(f) =0.53 (20:7:80, MeOH:NH₄ OH:CHCl₃)

EXAMPLE 33 Preparation of[S-(1R*,2S*)]-N,N'-[(Phenylmethyl)iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis-[N²-[(1,1-dimethylethoxy)carbonyl]-L-valinamide] (Compound 33) ##STR121##

To a solution of Compound 32 (≦0.185 mmol) and Boc-(L)-valine (87 mg,0.40 mmol) in CH₂ Cl₂ (2.0 mL) at 0° C. under argon was added EDCI (85mg, 0.44 mmol), HOBT (93 mg, 0.69 mmol), and 4-methylmorpholine (0.065mL). After 20 min at 0° C., the reaction mixture was stirred at RT for68 h. The reaction mixture was partitioned between EtOAc and saturatedNaHCO₃. The organic layer was extracted with brine, dried over Na₂ SO₄,and the volatiles were evaporated in vacuo to give an oily-solidresidue. This residue (140 mg) was purified by flash columnchromatography (silica gel, 2.5 by 13 cm), eluting with 0.5, 1, 2, 3, 4and then 12% MeOH:CH₂ Cl₂ to give the title Compound 33 (29.6 mg, 19%yield for the 2 steps) as a colorless solid. R_(f) =0.59 (15% MeOH:CH₂Cl₂).

EXAMPLE 34 Preparation of[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[N²-[(1,1-dimethylethoxy)carbonyl]-L-valinamide] (Compound 34) ##STR122##

Compound 33 was converted to the title Compound 34 by a procedureanalogous to the one used for the synthesis of. Compound 7.

m.p. 216°-222° C.; [α]_(D) ²⁵ =-28.55° (c 0.16, MeOH) . MS: 742 (M+H ) .Anal. Calc. for C₄₀ H₆₃ N₅ O₈ . 0.27 H₂ O: C, 64.32; H, 8.58; N, 9.38Found: C, 63.90; H, 8.49; N, 9.80

EXAMPLE 35 Preparation of[S-(1R*,2S*)]-N,N'-[[(Phenylmethyl)imino]bis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bisbenzamide(Compound 35) ##STR123##

To a suspension of Compound 32 (≦0.168 mmol) in CH₂ Cl₂ (1.5 mL) wasadded i-Pr₂ NEt (0.09 mL), resulting in a homogeneous solution. To thestirring reaction mixture at 0° C. was added 0.04 ml of benzoylchloride. A second portion of CH₂ Cl₂ (1.5 mL) and i-Pr₂ NEt (0.09 mL)was added after 30 min at 0° C. and the reaction mixture was stirred atRT for 1.5 h. At 0° C., the reaction mixture was quenched with saturatedNaHCO₃ and the aqueous layer was saturated with NaCl and extracted withEtOAc and CH₂ Cl₂. The combined organic layers were dried (Na₂ SO₄) andthe volatiles were evaporated in vacuo to a slightly yellow solidresidue which was purified by silica gel chromatography (2 by 10 cm),eluting with 8:2 EtOAc:CH₂ Cl₂, then EtOAc to give the title Compound 35(96 mg, 93% yield) as a colorless solid. R_(f) =0.60 (20:7:80 MeOH:NH₄OH:CHCl₃).

EXAMPLE 36 Preparation of[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bisbenzamide(Compound 36) ##STR124##

A mixture of Compound 35 (96 mg, 0.157 mmol) and Pd(OH)₂ (45 mg, 20% oncarbon) in aqueous HOAc (3 mL, 90%) at RT was stirred under a H₂atmosphere. After 7 h, a second portion of Pd(OH)₂ (6 mg) was added. Thereaction mixture was stirred for an additional 45 min and filteredthrough Celite, washing the filter pad thoroughly with aqueous HOAc. Thevolatiles were removed in vacuo to give a colorless solid which wastriturated twice with hot Et₂ O and once with hot EtOAc. The resultingresidue was purified by flash chromatography (silica gel, 1 by 11 cm),eluting with MeOH:NH₄ OH:CH₂ Cl₂ (1:0.1:9) to give the title Compound 36(50 mg, 58% yield) as a colorless solid.

m.p. dec. 227°-231° C.; [α]_(D) ²⁵ =-83.95° (c 0.21, DMSO); MS: 552(M+H). Anal. Calc. for C₃₄ H₃₇ N3O₄ : C, 74.02; H, 6.76; N, 7.62 Found:C, 73.88; H, 6.90; N, 7.62

EXAMPLE 37 Preparation of[S-(1R*,2S*)]-[[(Phenylmethyl)imino]bis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bisiminobis[N²-[(1,1-dimethylethoxy)carbonyl]-L-phenylalaninamide] (Compound 37)##STR125##

Compound 32 was coupled with Boc-L-phenylalanine by a procedureanalogous to the one used for the synthesis of Compound 33 (1:1 CH₂ Cl₂:DMF was used) to give the title Compound 37. R_(f) =0.78 (10% MeOH:CH₂Cl₂).

EXAMPLE 38 Preparation of [S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]-bisimino-bis[N²-[(1,1-dimethylethoxy)carbonyl]-L-phenyl-alaninamide] (Compound 38)##STR126##

Compound 37 was converted to the title Compound 38 by a procedureanalogous to the one used for the synthesis of Compound 36.

m.p. dec. 206°-212° C.; [α]_(D) ²⁵ =-14.28° (c 0.13, DMSO); MS:(CI/NH₃): 838 (M+H). Anal. Calc. for C₄₈ H₆₃ N₅ O₈ . 1.07 H₂ O: C,67.24; H, 7.66; N, 8.17 Found: C, 67.23; H, 7.26; N, 8.18

EXAMPLE 39 Preparation of[S-(1R*,2S*)]-N,N'-[[[(9H-Fluoren-9-ylmethoxy)carbonyl]imino]-bis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamicacid, bis (1,1-dimethylethyl)ester (Compound 39) ##STR127##

To a mixture of Compound 2 (192 mg, 0.354 mmol) in i-Pr₂ NEt (0.08 mL)and DMF (2 mL) at 0° C. was added 9-fluorenylmethyl chloroformate (100mg, 0.386 mmol). After 1 h at 0° C., the reaction mixture was stirred atRT for 2 h, quenched at 0° C. with saturated NaHCO₃, and extracted withEtOAc. The organic layer was dried (Na₂ SO₄) and the volatiles removedin vacuo to leave an oily-foam which was purified by flashchromatography (silica gel, 2.5 by 12 cm), eluting with 30% EtOAc:CH₂Cl₂ to give the title Compound 39 (251 mg, containing 8% by weight ofEtOAc by 1H NMR analysis, 85% yield) as an oily foam. R_(f) =0.33(35:65, EtOAc:CH₂ Cl₂).

EXAMPLE 40 Preparation of[R-(R*,S*)]-N,N-Bis(3-amino-2-hydroxy-4-phenylbutyl)carbamic acid,9H-fluoren-9-ylmethyl ester, hydrochloride salt (Compound 40) ##STR128##

Compound 39 was converted to the title Compound 40 by a procedureanalogous to the one used for the synthesis of Compound 32. R_(f) =0.56(20:6:80, MeOH:NH₄ OH:CHCl₃).

EXAMPLE 41 Preparation of [S-(1S*,2R*)]-N,N'-[[[(9H-Fluoren-9-ylmethoxy)carbonyl]imino]bis-[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bis[N² -[(phenylmethoxy)carbonyl]-L-valinamide] (Compound 41) ##STR129##

Compound 40 was coupled with Cbz-L-valine by a procedure analogous tothe one used for the synthesis of Compound 33 (DMF was used) to give thetitle Compound 41. R_(f) =0.69 (1:9, MeOH:CH₂ Cl₂).

EXAMPLE 42 Preparation of[1S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bis[N² -[(phenylmethoxy)carbonyl]-L-valinamide] (Compound 42) ##STR130##

To a mixture of Compound 41 (110 mg, 0.107 mmol) in DMF (4 mL) at RT wasadded piperidine (0.20 mL). After 50 min, the reaction mixture wasdiluted with H₂ O and the resulting solid was collected by filtrationand washed with H₂ O and hexanes. The resulting residue was purified byflash chromatography (silica gel, 2 by 13 cm), eluting with MeOH:NH₄OH:CH₂ Cl₂ (7:0.7:92.3, 8:0.8:91.2, and then 9:0.9:90.1) to give thetitle Compound 42 (65 mg, 75% yield) as a colorless solid.

m.p. dec. 217°-221° C.; [α]_(D) ²⁵ =-14.14° (c 0.21, DMSO); MS: 810(M+H) . Anal. Calc. for C₄₆ H59N₅ O₈ . 0.56 H₂ O: C, 67.37; H, 7.39; N,8.54 Found: C, 67.43; H, 7.17; N, 8.48

EXAMPLE 43 Preparation of[S-(1S*,2R*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis-L-valinamide(Compound 43) ##STR131##

A mixture of Compound 42 (65 mg, 81 μmol) and Pd(OH)₂ (23 mg) in aqueousHOAc (3 mL, 90%) at RT was stirred under an H₂ for 2.5 h, filteredthrough Celite, washing the filter pad with aqueous HOAc, and thevolatiles were removed in vacuo. The resulting oily-residue wasco-evaporated with dry Et₂ O to give a colorless solid (60 mg). Thisresidue was dissolved in H₂ O, basified to pH 9-10 with saturatedaqueous K₂ CO₃ and purified by CHP-20P resin chromatography, elutingwith H₂ O, then CH₃ CN:NH₄ OH:H₂ O and the column flushed with MeOH:NH₄OH:H₂ O to give the title Compound 43 (29 mg, ˜62% yield) as a slightlycolored solid. m.p. 115°-116° C. MS: 542 (M+H) .

EXAMPLE 44 Preparation of[R-(R*,S*)]-Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, bis(phenylmethyl) ester (Compound 44c)

(a) Compound 44a) ##STR132##

Compound 44a was prepared by procedures analogous to those used for thesynthesis of Compound 1b(i), in which N-Cbz-L-phenylalanine was employedin place of N-Boc-L-phenylalanine.

(b) Compound 44b ##STR133##

Compound 44a was converted into Compound 44b by a procedure analogous tothe one used for the synthesis of Compound 16b except that the reactionwas done in MeOH saturated with NH₃ at 55° C. for 40 h in a sealedbottle.

(c) Compound 44c ##STR134##

Compounds 44a and 44b (1 equivalent of each) were reacted by a procedureanalogous to that used for the preparation of Compound 4b to give thetitle Compound 44c (white solid).

mp 167°-171° C.; [α]_(D) =-27.7° (C 0.13, AcOH). Mass Spec. 612 (M+H).Analysis Calc. for C₃₆ H₄₁ N₃ O₆.1.43H₂ O: C, 67.82; H, 6.93; N, 6.59;Found: C, 68.12; H, 6.56; N, 6.29.

EXAMPLE 45 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy1-(phenylmethyl)-3,1-propandiyl]biscarbamicacid, 1,1-dimethylethyl phenylmethyl ester (Compound 45) ##STR135##

To a solution of lithium perchlorate (16.4 g, 0.155 mol) in 500 ml CH₃CN was added Compound 16b (43.5 g, 0.155 mol) as a solid followed byCompound 44a (41.2 g, 0.139 mole) in 150 ml CH₃ CN. The resultingmixture was stirred at 30° C. for 2 h and at 40° C. for 30 h at whichpoint it was cooled to RT then added to 1.5 L of H₂ O. The resultingprecipitate was filtered and triturated with i-PrOH followed by 1:1EtOAc:i-PrOH (2×) to give 42.1 g (52%) of Compound 45 as a white solid.

m.p. 169°-173°; [α]_(D) =-13.9° (c 1.3, MeOH).

EXAMPLE 46 Preparation of[R-(R*,S*)]-N,N"-[[(9H-Fluoren-9-ylmethoxy)carbonyl]iminobis-[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[N'-(1,1-dimethylethyl)urea](Compound 46) ##STR136##

To a suspension of Compound 40 (59 mg, 92 μmmol) in CH₂ Cl₂ (1 mL) wasadded Et₃ N (40 μL) followed by tert-butylisocyanate (20 mg, 0.201mmol). After 3 h, a second portion of tert-butylisocyanate (4.3 mg,0.044 mmol) was added and after a further 2 h the volatiles were removedin vacuo to leave a colorless solid. The residue was purified by flashchromatography (silica gel, 1 by 14 cm), eluting with 0.5, 3, and then4% MeOH:CH₂ Cl₂ to give the title Compound 46 (55 mg, 79% yield) as acolorless solid. R_(f) =0.56 (10:90, MeOH:CH₂ Cl₂) (PMA); Mass Spec.(FAB): 764 (M+H) .

EXAMPLE 47 Preparation of[R-(R*,S*)]-N,N"-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]-bis[N'-(1,1-dimethylethyl)urea] (Compound 47) ##STR137##

Compound 46 was converted to the title Compound 47 by a procedureanalogous to the one used for the synthesis of Compound 42.

m.p. 108°-110° C.; [α]_(D) ²⁵ =+1.93° (c 0.19, MeOH). MS: (CI): 542(M+H). Anal. Calc. for C₃₀ H₄₇ N₅ O₄ . 0.84 H₂ O: C, 64.70; H, 8.81; N,12.58 Found: C, 64.85; H, 8.71; N, 12.43

EXAMPLE 48 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[3-Amino-2-hydroxy-4-phenylbutyl)-[[2-(trimethylsilyl)ethoxy]carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1.1-dimethylethyl ester (Compound 48) ##STR138##

Compound 45 was converted to the title Compound 48 by a two-stepprocedure analogous to the coversion of Compound 17b to Compound 19(MeOH was used in removing the carbobenzyloxy group).

¹ H NMR (CD₃ OD): δ 0.05 (s, 9H), 1.03 (m, 2H), 1.30 (s, 9H), 2.60 (m,2H), 3.00 (m, 3H), 3.21 (m, 1H) , 3.45-3.82 (m's, 6H), 4.12 (m, 2H) ,7.11-7.28 (m, 10H).

EXAMPLE 49 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)amino]carbonyl]amino]-2-hydroxy-4-phenylbutyl][2-(trimethylsilyl)ethoxy]carbonyl]amino]-2-hydroxy]-1-(phenylmethyl]propyl]carbamic acid, 1,1-dimethylethyl ester(Compound 49) ##STR139##

Compound 48 was converted to the title Compound 49 by a procedureanalogous to that used for the synthesis of Compound 46.

¹ H NMR (CD₃ OD): δ 0.05 (s, 9H), 0.98 (m, 2H), 1.20 (s, 9H), 1.27 (s,9H), 2.65 (m, 2H), 3.05 (m, 2H), 3.25 (m, 2H), 3.60-3.85 (m's, 6H), 4.15(m, 2H), 7.10-7.30 (m, 10H) .

EXAMPLE 50 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)amino]carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 50) ##STR140##

Compound 49 was deprotected by a procedure analogous to the one used forthe synthesis of Compound 21 to give the title Compound 50.

mp 110°-112° C.; [α]_(D) =-3.5° (c 0.2, MeOH) . Mass Spec.: 543 (M+H) .Analysis calc. for C₃₀ H₄₆ N4O₅.1.39H₂ O: C, 63.46; H, 8.66; N, 9.87;Found: C, 63.78; H, 8.21; N, 9.55.

EXAMPLE 51 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl-L-valinamide (Compound 51) ##STR141##

EDC (44 mg; 0.23 mmol) was added to a solution of Cbz-valine (54 mg;0.23 mmol) and HOBT (35 mg; 0.23 mmol) in 1 ml of DMF at 0° C. Afterstirring at 0° C. for 1 h, Compound 48 (124 mg; 0.21 mmol) was added,followed by N-methylmorpholine (28 ml; 0.25 mmol ) . The reactionmixture was allowed to warm to RT and stir for 20 h, after which time itwas partitioned between EtOAc (30 ml) and H₂ O (30 ml). The organiclayer was washed with saturated aqueous KHSO₄ (2×), H₂ O, 1N NaOH (2×),H₂ O and brine. The organic layer was dried (MgSO₄), concentrated, andthe resulting residue purified by silica gel column chromatography(2.5×12 cm), eluting with 1:1 EtOAc:hexane to afford 137 mg (80%) ofCompound 51 as a white foam.

Mass Spec.: 821 (M+H).

EXAMPLE 52 Preparation of[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-amino]-2-hydroxy-1-(phenylmethyl)propyl-N²-[(phenylmethoxy)carbonyl]-L-valinamide (Compound 52) ##STR142##

Compound 51 was deprotected by a procedure analogous to the one used forthe synthesis of Compound 21 to give the title Compound 52 (white solid).

mp 202°-204° C.; [α]_(D) =-31.4° (c 0.07, AcOH). Mass Spec.: 677 (M+H) .Analysis calc. for C₃₈ H₅₂ N₄ O₇.0.22H₂ O: C, 67.04; H, 7.76; N, 8.23;Found: C, 67.01; H, 7.79; N, 8.26.

EXAMPLE 53 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)-carbonyl]-L-aspartamide (Compound 53) ##STR143##

The title Compound 53 was prepared from Compound 48 by a two-stepprocedure analogous to that used for the synthesis of Compound 52 exceptthat Cbz-asparagine was used.

mp 182°-185° C.; [α]_(D) =-26.7° (C 0.4, AcOH) High Resolution massspec.(M+H): 692.3665; calc'd for C₃₇ H₅₀ N₅ O₈ : 692.3659.

EXAMPLE 54 Preparation of[1S-[1R*,2S*(2S*,3R*)]-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 54) ##STR144##

A suspension of 1.0 g (1.73 mmol) of Compound 45 in 12 ml of EtOH and 6ml of cyclohexene along with 0.1 g of Pd(OH)₂ /C was stirred at reflux(oil bath temp.=85°) for 1 h. The reaction mixture was cooled to RT andfiltered through a plug of Celite on a nylon-66 filter and the filtrateevaporated to dryness to give 0.705 g (92%) of a white solid containingthe title Compound 54. ¹ H NMR (CD₃ OD): δ 1.30 (s, 9H), [1.18-rotamer],2.45-2.64 (m, 2H), 2.65-2.84 (m, 4H), 2.93-3.15 (m, 3H), 3.56-3.73 (m,3H), 7.10-7.36 (m, 10H).

EXAMPLE 55 Preparation of[1R*,2S*(2S*,3R*)]-N-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-phenylalaninamide (Compound 55) ##STR145##

EDC (38.4 mg, 0.20 mmol) was added to a solution of Cbz-phenylalanine(57.0 mg, 0.19 mmol) and HOBT (33.0 mg, 0.24 mmol) in CH₂ Cl₂ (0.8 mL)at 0° C. under argon. After stirring at 0° C. for 1 hr, Compound 54(77.0 mg, 0.17 mmol) was added in dry DMF (1.0 mL). The reaction mixturewas allowed to warm to RT and stirred overnight. The reaction wasdiluted with CH₂ Cl₂ (40 mL) and washed with saturated NaHCO₃ solution(15 mL), H₂ O (15 mL), and brine (15 mL), dried over MgSO₄, filtered,and concentrated. The crude material was purified by flashchromatography (silica gel; 1.5×15 cm) eluting with CH₂ Cl₂ :MeOH:NH₄ OH(gradient from 98.9:1:0.1 to 89:9:1) to give 76 mg of the title Compound55 (62%).

mp 185°-188° C.; [α]_(D) =-27.8° (C 0.2, MeOH) High Resolution massspec. (M+H)⁺ : 725.3906; Calc'd for C₄₂ H₅₃ N₄ O₇ : 725.3914.

EXAMPLE 56 Preparation of [S-[1R*,2S*(2S*,3R*)]-N²-[(1,1-Dimethylethoxy)carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-amino]-2-hydroxy-1-(phenylmethyl)-propyl]-L-phenylalaninamide (Compound 56) ##STR146##

The title Compound 56 was prepared from Compound 54 andBoc-phenylalanine by a procedure analogous to that used for thesynthesis of Compound 55.

mp 179°-182° C.; [α]_(D) =-14.4° (C 0.6, MeOH) Mass Spec.: (M+H)=691Analysis calculated for C₃₉ H₅₄ N₄ O₇.0.47 H₂ O: C, 66.90 H, 7.92 N,8.01 Found: C, 67.00 H, 7.64 N, 7.99

EXAMPLE 57 Preparation of[1R*,2S*(2S*,3R*)]-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[[[(phenylmethyl)amino]carbonyl]amino]butyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 57) ##STR147##

The title Compound 57 was prepared from Compound 48 by a two-stepprocedure analogous to the one used for the synthesis of Compound 50except that benzylisocyanate was used in place of tert-butylisocyanate.

mp 161°-165° C.; [α]_(D) =-11.9° (c 0.5, MeOH). Mass Spec. (M+H) 577Analysis calculated for C₃₃ H₄₄ N₄ O₅.0.40 H₂ O C, 67.88; H, 7.73; N,9.60; Found: C, 67.90; H, 7.59; N, 9.58.

EXAMPLE 58 Preparation of[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(1,1-dimethylethoxy)carbonyl]-L-valinamide (Compound 58) ##STR148##

The title Compound 58 (white solid) was prepared from Compound 48 by atwo-step procedure analogous to that used for the synthesis of Compound52 except that Boc-valine was used.

mp 182°-187° C.; [α]_(D) =-11.7° (c 0.06, AcOH). Mass Spec.: 642 (M+H) .Analysis calc. for C₃₅ H₅₄ N₄ O₇. 0.26H₂ O: C, 64.93; H, 8.49; N, 8.65;Found: C, 64.80; H, 8.35; N, 8.78.

EXAMPLE 59 Preparation of[S-[1R*,2S*(2S*,3R*)-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide(Compound 59) ##STR149##

The title Compound 59 (white solid) was prepared from Compound 52 by aprocedure analogous to the one used for the preparation of Compound 43.mp 131°-137° C.; [α]_(D) =+6.0° (C 0.2, MeOH). Mass Spec.: 543 (M+H) .Analysis calc. for C₃₀ H₄₆ N₄ O₅.1.14H₂ O: C, 63.97; H, 8.64; N, 9.95;Found: C, 63.96; H, 8.39; N, 9.96.

EXAMPLE 60 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,3-Dimethyl-1-oxybutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 60) ##STR150##

The title Compound 60 was prepared from Compound 48 by a two-stepprocedure analogous to that used for the synthesis of Compound 52 exceptthat tert-butylacetic acid was used in place of Cbz-valine (CH₂ Cl₂replaced DMF and no N-methyl morpholine was used in the EDC coupling).

mp 153°-156° C.; [α]^(rt) _(D) =-3.3° (C 0.1, MeOH) . Mass Spec.: 542(M+H) . Analysis calc. for C₃₁ H₄₇ N₃ O₅.0.54 H₂ O: C, 67.52; H, 8.79;N, 7.62; Found: C, 67.88; H, 8.80; N, 7.26.

EXAMPLE 61 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide(Compound 61) ##STR151##

A suspension of Compound 51 (385 mg; 0.47 mmol) and 110 mg of Pd(OH)₂ /Cin 5 ml of MeOH was stirred at RT under a H₂ atmosphere for 1.5 h. Thereaction mixture was filtered through a Nylon-66, 0.45 micron filter toremove the catalyst and the filtrate was concentrated to dryness. Theresidue was chromatographed on a 2.5×20 cm silica gel column, using 5%MeOH/CH₂ Cl₂ as the mobile phase to afford 306 mg (95%) of the titleCompound 61 as a white foam. ¹ H NMR (DMSO-d⁶ ; 60° C.): δ 0.02 (s, 9H),0.56 (J=7 Hz, 3H), 0.74 (d, J=7 Hz, 3H), 0.95 (t, J=7.5, 9.5 Hz, 2H),1.25 (s, 9H), 1.48 (brs, 2H), 1.80 (m, 1H), 2.62 (m, 2H), 2.87 (d, J=4.5Hz, 1H), 2.97 (m, 2H), 3.59 (m, 3H), 3.69 (m, 2H), 3.94 (m, 1H), 4.06(dd, J=7.5, 14.5 Hz, 2H), 4.87 (m, 1H), 4.97 (m, 1H), 6.37 (brs, 1H),7.14 (m, 2H), 7.20 (m, 10H), 7.57 (d, J=9 Hz, 1H).

EXAMPLE 62 Preparation of[1S-[1R*,2S*(2S*,3R*)]-N-[3S-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-phenylalanyl]-L-valinamide (Compound 62)##STR152##

The title Compound 62 (white solid) was prepared from Compound 61 andCbz-phenylalanine by a two-step procedure analogous to that used for theconversion of Compound 48 to Compound 52.

mp 215°-218° C.; [α]_(D) =-20.7° (C 0.15, AcOH) . Mass Spec.: (M+H=824).Analysis calc. for C₄₇ H₆₁ N₅ O₈.0.90 H₂ O: C, 67.19; H, 7.53; N, 8.33;Found: C, 67.25; H, 7.25; N, 8.27.

EXAMPLE 63 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(1-naphthalenyloxy)acetyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 63) ##STR153##

The title Compound 63 was prepared from Compound 48 by a two-stepprocedure analogous to that used for the synthesis of Compound 52 exceptthat (1-naphthoxy)acetic acid was used.

m.p. 182°-185° C.; [α]_(D) =-58.5° (c=0.19, MeOH). High Resolution MassSpec: (M+H=628.3397; C₃₇ H₄₆ N₃ O₆ ; 1.7 ppm error).

EXAMPLE 64 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[(2-naphthalenylcarbonyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 64) ##STR154##

The title Compound 64 was prepared from Compound 48 by a two-stepprocedure analogous to that used for the synthesis of Compound 52 exceptthat 2-naphthoic acid was used.

m.p. 188°-192° C.; [α]_(D) =-64.1° (c=0.19, MeOH). High Resolution MassSpec: (M+H=598.3292; C₃₆ H₄₄ N₃ O₅ ; 1.8 ppm error).

EXAMPLE 65 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[(2-quinolinylcarbonyl)amino]butyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 65) ##STR155##

The title Compound 65 was prepared Compound 48 by a two-step procedureanalogous to that used for the synthesis of Compound 52 except thatquinaldic acid was used.

m.p. 192°-196° C.; [α]_(D) =-67.2° (c=3.75, MeOH). High Resolution MassSpec: (M+H=599.3257; C₃₅ H₄₃ N₄ O₅ ; 4 ppm error).

EXAMPLE 66 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-methyl-N² [(phenylmethoxy)carbonyl]-L-valinamide (Compound 66b )

(a) Compound 66a ##STR156##

To a solution of N-Cbz-L-valine (2.51 g, 10.0 mmol) and CH₃ I (5.0 mL,80.0 mmol) in dry THF (30 mL) cooled at 0° C. was added Nail (0.90 g of80% dispersion in mineral oil, 30.0 mol) in portions. After theaddition, the suspension was stirred at RT for 12 h at which timeadditional CH₃ I (1.5 mL, 24.0 mmol) was added, followed by 0.25 g ofNaH (80%, 8.3 mmol). After the suspension was stirred

for an additional 24 h, EtOAc (50 mL) was added. The mixture was stirredfor 30 min at RT, and then cooled down to 0° C. H₂ O was added dropwiseto destroy NaH. The solvents were removed in vacuo, the oily residualpartitioned between H₂ O and Et₂ O, and the aqueous layer extracted withEt₂ O. The combined Et₂ O solution was extracted with 40% aqueous NaHCO₃and the combined aqueous phase acidified with 4N HCl to pH 2 andextracted with EtOAc. The EtOAc extracts were washed with H₂ O, 5%aqueous NaS₂ O₃, H₂ O, dried over MgSO₄ and evaporated in vacuo todryness to give a pale yellow oil, which was crystallized from Et₂ O andpentane to afford white crystalline Compound 66a.

(2.97 g, 97%). mp. 66°-67° C.

(b) Compound 66b ##STR157##

The title Compound 66b was prepared from Compounds 54 and 66a by aprocedure analogous to the one used for the synthesis of Compound 55 (1eq. of N-methylmorpholine was added along with Compound 54).

mp 67°-70° C.; [α]^(rt) _(D) =-59.3° (c 0.8, MeOH). Mass Spec. FAB[M+H]⁺ : 691. Analysis calc. for C₃₉ H₅₄ N₄ O₇.1.15 H₂ O: C, 65.84; H,7.97; N, 7.87; Found: C, 65.94; H, 7.62; N, 7.77.

EXAMPLE 67 Preparation of [S-[1R*,2S*(2S*,3R*)]]-N²-[[2,3-Dihydro-1H-inden-1-yl)oxy]carbonyl-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide(Compound 67c)

(a) Compound 67a ##STR158##

To a solution of 537 mg (4.00 mmol) of (±)-1-indanol in 20 ml of dry CH₂Cl₂ at 0° C. were added 1.01 g (5.00 mmol) of p-nitrophenylchloroformate and 0.70 mL of Et₃ N. The mixture was stirred for 2 h at0° C. and for 2 h at RT. The reaction mixture was diluted with 100 mL ofCH₂ Cl₂, and washed with 5% KHSO₄ (50 mL), 0.1N NaOH (2×50 mL) andsaturated NaCl (50 mL). The organic layer was dried over Na₂ SO₄,filtered, and concentrated in vacuo. Flash chromatography of the residueon silica gel (CC-7; buffered, pH=7), eluting with 0-10% EtOAc-hexane,provided 1.24 g (˜100%) of Compound 62a, as a white solid.

(b) Compound 67b ##STR159##

A suspension of 117 mg (1.00 mmol) of L-valine in 1 mL of 1.0N NaOH wasstirred for 30 min and then treated with a solution of 299 mg (1.00mmol) of Compound 67a in 2 mL of t-butanol and 1 mL of dioxane. Thereaction mixture was stirred at RT overnight. 0.2 mL of Et₃ N was addedto the mixture to increase the rate of the reaction and stirring wascontinued for 48 h. The reaction mixture was diluted with 50 mL ofEtOAc, and washed with 5% KHSO₄ (2×25 mL), and saturated NaCl (25 mL).The organic layer was dried over Na₂ SO₄, filtered, and concentrated invacuo to provide 355 mg of crude acid. Flash chromatography on silicagel, eluting with 50% EtOAc-hexane and then 50% EtOAc-hexane with 0.5%HOAc, afforded 209 mg (75%) of Compound 67b, as a white solid.

(c) Compound 67c ##STR160##

The title Compound 67c was prepared as a mixture of diastereomers fromCompound 54 and Compound 67b by a procedure analogous to that used forthe synthesis of Compound 55.

mp 202°-206° C.; [α]²⁰ _(D) =-15° (c=0.071, CH₃ OH) Mass Spec. 703(M+H)⁺ Elemental Analysis (%) C₄₀ H₅₄ N₄ O₇

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              68.35  68.13                                                   H              7.74   7.84                                                    N              7.97   7.70                                                    ______________________________________                                    

EXAMPLE 68 Preparation of [S-[1R*,2S*(2S*,3R*)]]-N²-[(1,1'-Biphenyl]-4-ylmethoxy]carbonyl-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide(Compound 68) ##STR161##

The title Compound 68 was prepared from Compound 54 by a three-stepprocedure analogous to that used for the synthesis of Compound 67cexcept that 4-biphenylmethanol was used in the first step and 1.1 eq. ofEt₃ N (no t-BuOH) was used in the second step.

mp 208°-211° C.; [α]²⁰ _(D) =-19° (c=0. 077, CH₃ OH) Mass Spec. 753(M+H)⁺ Elemental Analysis (%) C₄₄ H₅₆ N₄ O₇

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              70.19  69.91                                                   H              7.50   7.48                                                    N              7.44   7.23                                                    ______________________________________                                    

EXAMPLE 69 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-2-Hydroxy-3-[[2-hydroxy-3-[[[methyl(phenylmethyl)amino]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 69) ##STR162##

The title Compound 69 (white solid) was prepared from Compound 48 andN-benzyl-N-methyl carbamoyl chloride (Bull. Chem. Soc. Jpn., 50, 1872(1977)) by a two-step procedure analogous to that used for the synthesisof Compound 50.

mp 97°-99° C.; [α]_(D) =-18.8° (C 0.5, CH₃ OH). Mass Spec.(FAB) (M+H)⁺=591 Analysis calc. for C₃₄ H₄₆ N₄ O₅.0.89H₂ O: Calculated C, 67.31; H,7.94; N, 9.23; Found: C, 67.42; H, 7.83; N, 9.12.

EXAMPLE 70

Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylothoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(2-pyridinylmethoxy)carbonyl]-L-valinamide

(Compound 70d)

(a) Compounds 70a(i) and 70a(ii) ##STR163##

To a solution of L-valine methyl ester hydrochloride (2.5 g; 14.9 mmol)in 14.9 mL of dry dioxane was added trichloromethyl chloroformate (1.5g; 7.6 mmol) at RT. The mixture was heated at 60° C. for 3.5 h. Theclear solution was cooled to RT and concentrated in vacuo to give anoil, which was azeotroped from dry toluene (2×10 mL) to give Compounds70a(i) and 70a(ii).

(b) Compound 70b ##STR164##

To a solution of the crude Compounds 70a(i) and 70a(ii) (2.3 g; 14.9mmol) in 48 mL of dry toluene was added 1.6 g (14.9 mmol) of2-pyridylcarbinol. The mixture was heated to reflux for 12 h and thenconcentrated in vacuo to a residue. Purification by flash chromatography(silica gel; 25% acetone-hexane) afforded 1.08 g (27% over two steps) ofCompound 70b.

(c) Compound 70c ##STR165##

To a solution of Compound 70b (223 mg; 0.83 mmol) in 3.3 mL of drydioxane was added 3.0 mL of 0.5M LiOH. After 12 h at RT, the reactionmixture was acidified with 1N HCl (1.5 ml) and then evaporated todryness. Further drying over P₂ O₅ under vacuum at RT gave 300 mg(˜100%) of a brown residue containing Compound 70c.

(d) Compound 70d ##STR166##

The title Compound 70d was prepared from Compounds 54 and crude 70c by aprocedure analogous to that used for the synthesis of Compound 55 (1 eq.of N-methylmorpholine was used).

m.p. 175°-178° C.; [(α]^(rt) _(D) =-16.0° (c 0.13, MeOH). Mass spec.(M+H) 678 Elemental Analysis (%) C₃₇ H₅₁ N₅ O₇.2.90 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              60.87  60.84                                                   H              7.54   7.30                                                    N              9.59   9.57                                                    ______________________________________                                    

EXAMPLE 71 Preparation of[R-[1S*,2R*(2R*,3S*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-phenylmethyl)propyl]-N² -[(phenylmethoxy)carbonyl]-D-valinamide (Compound 71)##STR167##

The title Compound 71 was prepared from Compounds 54 and N-Cbz-D-valineby a procedure analogous to that used for the synthesis of Compound 55.

mp 185°-187° C.; [α]^(rt) _(D) =+16.25° (c 0.16, MeOH ) . Mass Spec. FAB[M+H]⁺ : 677. Analysis calc. for C₃₈ H₅₂ N₄ O₇. 1.63 H₂ O: C, 64.63; H,7.89; N, 7.93; Found: C, 64.63; H, 7.70; N, 8.12.

EXAMPLE 72 Preparation of 1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[(phenoxyacetyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 72) ##STR168##

The title Compound 72 (white solid) was prepared from Compounds 54 andphenoxyacetic acid by a procedure analogous to that used for thesynthesis of Compound 55 (1 eq. of N-methylmorpholine was used).

mp 162°-165° C.; [α]_(D) =-17.6° (C 0.5, CH₃ OH). Mass Spec.(FAB) (M+H)⁺=578 Analysis calc. for C₃₃ H₄₃ N₃ O₆ : Calculated C, 68.61; H, 7.50; N,7.27; Found: C, 68.59; H, 7.58; N, 7.33.

EXAMPLE 73 Preparation of[(S,R)-3-[[(R,S)-3-[[2-[[(Phenylmethoxy)carbonyl)amino]-2,3-dimethyl-1-oxybutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 73d )

(a) Compound 73a ##STR169##

A suspension of N-Cbz-L-Valine (2.51 g, 10.0 mmol), paraformaldehyde(2.0 g) and p-toluene-sulfonic acid (0.2 g) in 200 mL of toluene washeated to reflux for 2 h. After being cooled down to RT, the reactionmixture was washed with saturated NaHCO₃, brine and dried over MgSO₄.The filtrate was concentrated in vacuo to afford 2.32 g (88%) ofCompound 73a as a light yellow solid.

(b) Compound 73b ##STR170##

To a solution of crude Compound 73a (0.76 g; 2.88 mmol) in 10 ml of dryTHF cooled at -78° C. was added 6.62 ml (3.31 mmol) of KN(TMS)₂ (0.5Msolution in toluene) dropwise over 15 min. The reaction mixture wasstirred at the same temperature for 15 min, then CH₃ I (0.216 ml, 3.46mmol) was added dropwise. The mixture was stirred at -78° C. for 20 min,-20° C. for 20 min, then at 0° C. for 1 h. The reaction was quenchedwith 10 ml pH 7 buffer, and extracted with CH₂ Cl₂ (2×50 ml). Thecombined organics were washed with H₂ O, brine and dried over MgSO₄. Thefiltrate was concentrated to dryness and the oily residue purified byflash chromatography (silica gel), using 20% EtOAc/hexane as the mobilephase to afford 0.487 g (61%) of Compound 73b as a colorless oil.

(c) Compound 73c ##STR171##

A solution of Compound 73b (0.46 g, 1.66 mmol) in 5 ml of MeOH and 5 mlof 1N NaOH was heated at 55° C. for 30 min. After removal of MeOH, theaqueous phase was acidified to pH 1-2 with 1N HCl and extracted with CH₂Cl₂ (2×30 ml). The combined CH₂ Cl₂ phase was washed with water, brineand dried over MgSO₄ to give after concentrating in vacuo 0.44 g (100%)of Compound 73c as a colorless oil.

(d) Compound 73d ##STR172##

The title Compound 73d was prepared as a 1:1 mixture of diastereomersfrom Compounds 54 and 73c by a procedure analogous to that used for thesynthesis of Compound 55.

mp 66°-68° C.; [α]^(rt) _(D) =-5.6° (c 0.25, MeOH). Mass Spec. [M+H]⁺ :691. Analysis calc. for C₃₉ H₅₄ N₄ O₇. 0.46 H₂ O: C, 67.00; H, 7.92; N,8.01; Found: C, 66.88; H, 7.88; N, 8.13. The diastereomers (at positionindicated by an asterisk) were then separated by HPLC.

EXAMPLE 74 Preparation of [[R-(R*,S*)]-1,1'-Iminobis(3-amino-4-phenyl-2-butanol), trihydrochloride (Compound 74) ##STR173##

The title Compound 74 was prepared from Compound 2 by a procedureanalogous to that used for the synthesis of Compound 32. R_(f) =0.054(20:2:78 MeOH:NH₄ OH:CH₂ Cl₂).

EXAMPLE 75 Preparation of[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bis[N² -[[methyl(2-pyridinylmethyl)amino]carbonyl]L-valinamide (Compound75f)

(a) Compound 75a ##STR174##

To a solution of di-tert-butyldicarbonate (63 g, 0.29 mole) in 600 ml ofCH₂ Cl₂ at 0° C. was added a solution of 2-(aminomethyl)pyridine (31.36g, 0.29 mole) in 150 ml of CH₂ Cl₂ in a dropwise manner. After theaddition was complete the mixture was allowed to slowly warm to RT andstir overnight. The reaction was washed with H₂ O (3×800 ml), brine (800ml) and dried (Na₂ SO₄) to give, after concentration, 58.6 g (97%) ofCompound 75a as a pale yellow oil.

(b) Compound 75b ##STR175##

Compound 75a was converted to Compound 75b by a procedure analogous tothat used for the synthesis of Compound 66a except that DMF was used inplace of THF.

(c) Compound 75c ##STR176##

Compound 75b was converted to Compound 75c by a procedure analogous tothat used for the synthesis of Compound 32 except that the reaction wasrun at 40° C.

(d) Compound 75d ##STR177##

Compound 75c was converted to Compound 75d by a procedure analogous tothat used for the synthesis of Compound 70b except that CH₂ Cl₂ replacedtoluene and 2.5 eq. of N-methylmorpholine was added.

(e) Compound 75e ##STR178##

Compound 75d was converted to Compound 75e by a procedure analogous tothat used for the synthesis of Compound 70c (the reaction was quenchedwith one equivalent of 1N HCl).

(f) Compound 75f ##STR179##

A mixture of Compound 74 (136 mg, 0.25 mmol), HOBT (84 mg, 0.55 mmol),and Compound 75e (148 mg, 0.55 mmol) in 0.6 ml of dry DMF was cooled to0° C. EDCI (108 mg, 0.55 mmol) was added followed by 6 eq. ofN-methylmorpholine (167 mg, 3.3 mmol). The mixture was stirred at 0° C.for several hours and was then allowed to slowly warm to RT and stirovernight. The DMF was removed in vacuo and the residue was partitionedbetween saturated NaHCO₃ (10 ml) and EtOAc (15 ml). The EtOAc layer waswashed with additional saturated NaHCO₃, brine, dried over MgSO₄ andevaporated to give a crude yellow solid which purified on a 30 ml silicacolumn (CC-7, pH 6.8) eluting with 5%-10% MeOH/CH₂ Cl₂ +0.1% NH₄ OH toafford 86 mg (41%) of the title Compound 75f as a colorless solid.

m.p. 178°-182° C.; [α]_(D) =-22.4° (c,0.25, MeOH) Analysis calc. for C₄₆H₆₃ N₉ O₆. 2.0 H₂ O: C, 63.21; H, 7.73; N, 14.42; Found: C, 63.51; H,7.52; N, 14.12.

EXAMPLE 76 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²[[methyl(2-pyridinylmethyl)amino]carbonyl]-L-valinamide (Compound 76)##STR180##

To a solution of Compound 54 (111 mg, 0.25 mmol), HOBT (42 mg, 0.275mmol), and Compound 75e (74 mg, 0.275 mmol) in dry DMF (0.5 ml) at 0° C.was added EDCI (53 mg, 0.275 mmol) followed immediately byN-methylmorpholine (91 μl, 83 mg, 0.825 mmol). The reaction was stirredseveral hours at 0° C. and was then slowly warmed to RT and stirredovernight. The DMF was removed in vacuo and the resulting residue waspartitioned between EtOAc (10 ml) and H₂ O (10 ml). The organic layerwas washed with saturated NaHCO₃ and brine, dried over MgSO₄ andconcentrated to give a crude product which was purified on a 20 ml CC-7silica column (Silica pH 6.8) eluting with 3%→10% MeOH/CH₂ Cl₂ +0.1% NH₄OH to afford a glasslike residue. Lyophilization from dioxane/H₂ O gave48 mg (28%) of Compound 76 as a colorless solid.

m.p. 184°-188° C.; [α]_(D) =-16.4° (c=0.2, MeOH) High Resolution MassSpec. (FAB): C₃₈ H₅₅ N₆ O₆ =691.4183; Δ=0.35 ppm.

EXAMPLE 77 Preparation of [S-[1R*,2S*[2S*,3R*,N² -R*]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-hydroxy-1-oxo-3-phenylpropyl)-L-valinamide (Compound 77) ##STR181##

The title Compound 77 (white solid) was prepared from Compound 61 andL-phenyllactic acid by a two-step procedure analogous to that used forthe conversion of Compound 48 to Compound 52.

mp 176°-178° C.; [α]_(D) =-49.5° (C 0.16, MeOH). Mass Spec. FAB+ ion:(M+H)=691. Analysis calc. for C₃₉ H₅₄ N₄ O₇.0.61 H₂ O: C, 66.75; H,7.93; N, 7.98; Found: C, 66.81; H, 7.69; N, 7.92.

EXAMPLE 78 Preparation of [S-[1R*,2S*[2S*,3R*,N²-S*[-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-hydroxy-1-oxo-3-phenylpropyl)-L-valinamide (Compound 78) ##STR182##

The title Compound 78 (white solid) was prepared from Compound 61 andD-phenyllactic acid by a two-step procedure analogous to that used forthe conversion of Compound 48 to Compound 52.

mp 188°-194° C.; [α]_(D) =+7.6° (c 0.17, MeOH). Mass Spec. FAB+ ion:(M+H)=691. Analysis calc. for C₃₉ H₅₄ N₄ O₇.1.42 H₂ O: C, 65.38; H,8.00; N, 7.82; Found: C, 65.26; H, 7.84; N, 7.94.

EXAMPLE 79 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-naphthalenylcarbonyl)-L-valinamide (Compound 79) ##STR183##

The title Compound 79 was prepared from Compound 61 and 2-naphthoic acidby a two-step procedure analogous to that used for the conversion ofCompound 48 to Compound 52.

m.p. 192°-196° C.; [α]_(D) =-12.6° (C=0.18, MeOH) Analysis: calc. forC₄₁ H₅₂ N₄ O₆.0.6 H₂ O: C, 69.59; H, 7.58; N, 7.92; Found: C, 69.64; H,7.59; N, 7.87.

EXAMPLE 80 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-quinolinylcarbonyl)-L-valinamide (Compound 80) ##STR184##

The title Compound 80 was prepared from Compound 61 and quinaldic acidby a two-step procedure analogous to that used for the conversion ofCompound 48 to Compound 52.

m.p. 192°-194° C.; [α]_(D) =-14.5° (c=0.24, MeOH) Analysis calc. for C₄₀H₅₁ N₅ O₆. 0.64 H₂ O: C, 67.73; H, 7.43; N, 9.87; Found: C, 67.98; H,7.56; N, 9.62.

EXAMPLE 81 Preparation of [2R-[2R*(2S*,3S*),3S*]]-1,1'-Iminobis(3-amino-4-phenyl-2-butanol)hydrochloride (Compound 81) ##STR185##

The title Compound 81 was prepared as a tri-HCl salt from Compound 5 bya procedure analogous to that used for the synthesis of Compound 32.

R_(f) =0.07 (15:1.5:84.5 MeOH:NH₄ OH:CH₂ Cl₂).

EXAMPLE 82 Preparation of[S-[1R*,2R*(2S*,3R*)]]-N-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[[[N-(phenylmethoxy)carbonyl]-L-valyl]amino]butyl]amino]-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-valinamide (Compound 82) ##STR186##

The title Compound 82 was prepared from Compound 81 and Cbz-L-valine bya procedure analogous to that used for the synthesis of Compound 75f.

m.p. 216°-219° C.; [α]_(D) ²⁵ =-34.8° (c 0.28, DMSO). Mass Spec.: (FAB):810 (M+H). Anal. Calc. for C₄₆ H₅₉ N₅ O₈ : C, 68.21; H, 7.34; N, 8.65Found: C, 67.88; H, 7.50; N, 8.64

EXAMPLE 83 Preparation of[R-(R*,S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bisbenzeneacetamide(Compound 83) ##STR187##

The title Compound 83 was prepared from Compound 74 and phenylaceticacid by a procedure analogous to that used for the synthesis of Compound75f.

m.p dec. 216°-221° C; [α]_(D) ²⁵ =+11.4° (c 0.22, DMSO). MS: (CI/NH₃):580 (M+H) . Anal. Calc. for C₃₆ H₄₁ N₃ O₄.0.3 H₂ O: C, 73.90; H, 7.17;N, 7.18 Found: C, 73.88; H, 7.03; 7.20

EXAMPLE 84 Preparation of[S-[1R*,2S*(2S*,3R*)]-N-[N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl)-L-valyl]-L-phenylalanamide,fumarate (2:3) salt ##STR188##

A solution of Compound 62 (153 mg; 0.185 mmol) in 2 ml of HOAc wasstirred for 1 h over 20% Pd(OH)₂ /C (50 mg) at RT under a H₂ atmosphere(balloon). The catalyst was removed by filtration through a 0.45 micronNylon-66 filter and the filtrate was concentrated to dryness. Theresidue was dissolved in 5 ml of MeOH and fumaric acid (43 mg; 0.370mmol) was added as a solution in hot MeOH. The MeOH was removed in vacuoand the residual HOAc was azeotroped with heptane. After drying underhigh vacuum for several hours, the solid was dissolved in ˜2 ml of MeOHand Et₂ O (˜12 ml) was added dropwise with rapid stirring. The resultingsuspension was filtered and dried under high vacuum at 60° C. for 48 hto give 149 mg (93%) of Compound 84 as a white powder.

mp 125°-136° C.; [α]_(D) =-20.7 (c 0.15, MeOH). Mass Spec. FAB+ions:M+H=690. Analysis calc. for C₃₉ H₅₅ N₅ O₆. 1.5 C₄ H₄ O₄. 0.52 H₂ O: C,61.89; H, 7.16; N, 8.02; Found: C, 61.91; H, 7.23; N, 8.00.

EXAMPLE 85 Preparation of [S-(1R*,2S*,3R*)]-N²-[3-[[(Phenylmethoxy)carbonyl]amino]-1-oxo-3-phenylpropyl)-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenyl-butyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]-L-valinamide(Compound 85b )

(a) Compound 85a ##STR189##

Benzylchloroformate (1.0 ml; 6.70 mmol) and 2N NaOH (3.1 ml; 6.2 mmol)were alternately added over 5 min to a vigorously stirred solution of3-amino-3-phenylpropionic acid (1.0 g; 6.05 mmol) in 3.05 ml of 2N NaOHat 0° C. The mixture was stirred for 30 min at 0° C. and 30 min at RT.1N NaOH (10 ml) and water (50 ml) were added and the reaction mixturewas washed with Et₂ O (3×50 ml). After acidifying the aqueous layer topH<1 with 6N HCl, it was extracted with Et₂ O. The Et₂ O layer waswashed with H₂ O and brine, dried over MgSO₄, and concentrated to awhite solid which was recrystallized from EtOAc:hexane, 1:1 to afford1.02 g (61% ) of Compound 85a.

(b) Compound 85b ##STR190##

The title Compound 85b (white solid) was prepared as a mixture ofdiastereomers (at carbon marked with an asterisk) from Compounds 61 and85a by a two-step procedure analogous to that used for the conversion ofCompound 48 to Compound 52. ¹ H NMR (DMSO-d⁶ ; 70° C.): δ 0.57 (d, J=7Hz, 1.5H), 0.63 (d, J=7 Hz, 1.5H) , 0.69 (d, J=7 Hz, 1.5H) , 0.72 (d,J=7 Hz, 1.5H), 1.25 (s, 9H), 2.56 (m, 8H), 2.95 (m, 2H), 3.43 (m, 2H),3.57 (m, 1H), 3.91 (m, 1H), 4.04 (m, 2H), 4.55 (brs, 1H), 4.97 (m, 3H),6.33 (brs, 1H), 7.25 (m, 20H), 7.50 (m, 2H), 7.56 (d, 8.5 Hz, 1H).

EXAMPLE 86 Preparation of [S-[1R*,2S*(2S*,3R*)]-N²-(3-Amino-1-oxo-3-phenylpropyl)-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide,fumarate (2:3) salt (Compound 86) ##STR191##

Compound 85b was converted to the title Compound 86 (white solid) by aprocedure analogous to that used for the synthesis of Compound 84.

mp 138°-146° C.; [α]_(D) =-13.0 (c 0.2, MeOH). Mass Spec. FAB+ ion:(M+H)=690. Analysis calc. for C₃₉ H₅₅ N₅ O₆.1.5 C₄ H₄ O₄.0.92 H₂ O: C,61.98; H, 7.15; N, 8.03; Found: C, 61.95; H, 7.21; N, 8.06.

EXAMPLE 87 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[[1-[[(phenylmethoxy)carbonyl]amino]cyclopentyl]carbonyl]amino]-4-phenylbutyl]-amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 87b )

(a) Compound 87a ##STR192##

Compound 87a was prepared from 1-aminocyclopentanecarboxylic acid(cycloleucine) by a procedure analogous to that used for the synthesisof Compound 85a.

(b) Compound 87b ##STR193##

The title Compound 87b was prepared from Compounds 54 and 87a by aprocedure analogous to that used for the synthesis of Compound 55.

mp 70°-73° C.; [α]_(D) =+9° (c 0.2, MeOH); Mass Spec: FAB (M+H)+: 689.Analysis calculated for C₃₈ H₅₂ N₄ O₇.0.65H₂ O C, 66.87; H, 7.67; N,8.00; Found: C, 66.82; H, 7.58; N, 8.05.

EXAMPLE 88 Preparation of[1S-[1R*-[1R*,2S*(2S*,3R*)]]]-2,2-Dimethyl-1-[[[3-[[3-[[(1,1-Dimethylethoxy)carbonylamino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamic acid,phenylmethyl ester (Compound 88b)

(a) Compound 88a ##STR194##

Compound 88a was prepared from L-tert-leucine by a procedure analogousto that used for the synthesis of Compound 85a.

(b) Compound 88b ##STR195##

The title Compound 88b was prepared from Compounds 54 and 88a by aprocedure analogous to that used for the synthesis of Compound 55 (DMFonly was used along with 1 equivalent of N-methylmorpholine).

m.p. 144°-147°; [α]_(D) ²⁵ =-14.8° (c 0.15, MeOH) {[α]₃₆₅ =-62.7° (c0.15, MeOH)}. Mass Spec.: (FAB/SIMS): 691 (M+H) . Analysis Calc. For C₃₉H₅₄ N₄. 0.13 H₂ O: C,67.58; H,7.89; N,8.08 Found: C,67.32; H,7.76;N,8.34

EXAMPLE 89 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-lysinamide (Compound 89b )

(a) Compound 89a ##STR196##

Compound 89a was prepared from α-N-Cbz-L-lysine andtrimethylsilylethylchloroformate by a procedure analogous to that usedfor the synthesis of Compound 85a.

(b) Compound 89b ##STR197##

The title Compound 89b (white solid) was prepared from Compounds 48 and89a by a two-step procedure analogous to that used for the synthesis ofCompound 52 (6 equivalents of n-Bu₄ NF was used).

mp 129°-131° C.; [α]_(D) =-19.4° (c 0.35, MeOH). Mass Spec. FAB+ion:(M+H)=706. Analysis calc. for C₃₉ H₅₅ N₅ O₇.1.49H₂ O: C, 63.93; H, 7.98;N, 9.56; Found: C, 64.01; H, 7.68; N, 9.48.

EXAMPLE 90 Preparation of[S-(1R*,2S*]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[L-valinamide], trihydrochloride (Compound 90) ##STR198##

The title Compound 90 was prepared from Compound 34 by a procedureanalogous to that used for the synthesis of Compound 32. R_(f) =0.29(20:2:78 MeOH:NH₄ OH:CH₂ Cl₂) .

EXAMPLE 91 Preparation of[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[N² -[N-[(1,1-dimethoxyethyl)carbonyl]-L-phenylalanyl]-L-valinamide](Compound 91) ##STR199##

The title Compound 91 was prepared from Compound 90 andBoc-L-phenylalanine by a procedure analogous to that used for thesynthesis of Compound 75f. R_(f) =0.31 (10:1:89 MeOH:NH₄ OH:CH₂ Cl₂).MS: (FAB): 1036 (M+H).

EXAMPLE 92 Preparation of[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bis[N² -(L-phenylalanyl)-L-valinamide], trihydrochloride (Compound 92)##STR200##

Compound 91 (81 mg; 78.2 μmol) was stirred with methanolic HCl (1 ml of2.09M solution) at 0° C. for 30 min and at RT for 2 h. The volatileswere removed and the residue evaporated from Et₂ O and dried under highvacuum overnight. The resulting solid was dissolved in MeOH andprecipitated with Et₂ O after which it was triturated with Et₂ O andEtOAc to give 62 mg (86%) of a light-orange colored solid.

m.p. dec. 180°-187° C.; [α]_(D) ²⁵ =-16.5° (c 0.12, MeOH); MS: (FAB):836 (M+H) . Anal. Calc. for C₄₈ H₆₈ C₁₃ N₇ O₆ . 2.58 H₂ O: C, 58.13; H,7.43; N, 9.88 Found: C, 58.20; H, 7.33; N, 9.81

EXAMPLE 93 Preparation of [S-[1R*,2S*(2S*,3R*)]]-N,[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(1H-benzimidazol-2-ylmethoxy) carbonyl]-L-valinamide (Compound 93f )

(a) Compound 93a ##STR201##

A mixture of 3.24 g (30.0 mmol) of σ-phenylenediamine and 3.42 g (45.0mmol) of glycolic acid in 30 mL of 4N HCl was heated at reflux for 45min. The resulting solution was cooled to RT and basified (pH=8) withNH₄ OH. The resulting suspension was cooled in an ice bath, and thesolid filtered, rinsed with cold H₂ O and recrystallized from H₂ O toafford 2.70 g (61%) of Compound 93a as a tan solid.

(b) Compound 93b ##STR202##

To a solution of 500 mg (3.37 mmol) of Compound 93a in 5 mL of DMF wereadded 357 mg (3.37 mmol) of Na₂ CO₃ and 0.58 mL (3.37 mmol; 80% pure) ofbenzyl chloromethyl ether. The mixture was stirred at 0° C. for 1 h andat RT for 24 h. The mixture was partitioned between EtOAc and H₂ O, andthe combined organic extracts dried over Na₂ SO₄, filtered, andconcentrated in vacuo to give 945 mg of crude material. Flashchromatography on silica gel (25-100% EtOAc-hexane; then, 5% CH₃OH-EtOAc) provided 339 mg (39%) of Compound 93b.

(c) Compound 93c ##STR203##

To a solution of 260 mg (1.01 mmol) of Compound 93b in 3 mL of CH₂ Cl₂and 1.5 mL of pyridine at 0° C. was added 214 mg (1.06 mmol) ofp-nitrophenylchloroformate in 1.5 mL of CH₂ Cl₂. The mixture was stirredat 0° C. for 1 h and at RT for 3 h, diluted with 100 mL of EtOAc andwashed with 1M NaOH (3×25 mL), H₂ O (2×25 mL), and brine (25 mL). Theorganic layer was dried over MgSO₄, filtered, and concentrated in vacuoaffording 396 mg of Compound 93c.

(d) Compound 93d ##STR204##

To a solution of 105 mg (0.893 mmol) of L-valine in 0.9 mL of 1.0N NaOHwas added a solution of 387 mg (0.893 mmol) of Compound 93c in 3 mL ofdioxane and 0.2 mL of Et₃ N. The mixture was stirred at RT for 18 h andpartitioned between EtOAc and H₂ O. The aqueous layer was acidified topH=4 with 5% KHSO₄ and extracted with EtOAc (2×25 mL). The combinedorganic extracts were dried over Na₂ SO₄, filtered, and evaporated invacuo to provide 0.79 g of crude acid. Flash chromatography on silicagel, eluting with 50% EtOAc-hexane and then 10% MeOH-CHCl₃, afforded 151mg (41%) of Compound 93d.

(e) Compound 93e ##STR205##

To a solution of 242 mg (0.588 mmol) of Compound 93d in 3 mL of MeOH wasadded a solution of HCl (0.74 mmol) in 5 mL of MeOH and 200 mg ofPd(OH)₂. The mixture was stirred under a H₂ atmosphere (balloon) for 4 hat which time an additional 0.1 mL of 1N HCl and 50 mg of Pd(OH)₂ wasadded. The mixture was stirred under a H₂ atmosphere for another 2.5 hand then filtered and evaporated in vacuo. Re-evaporation in vacuo fromCHCl₃ /Et₂ O afforded 326 mg of crude Compound 93e as an HCl salt.

(f) Compound 93f ##STR206##

To a solution of 270 mg (˜0.488 mmol; ca. 60% pure, contaminated withsolvent) of Compound 93e in 3 mL of dry DMF at 0° C. were added 228 mg(0.488 mmol) of Compound 54, 99 mg (0.73 mmol) of HOBT, 110 μL ofN-methylmorpholine, and 104 mg (0.54 mmol) of EDC. The mixture wasstirred at RT for 18 h, diluted with 100 mL of EtOAc, and washed withsaturated NaHCO₃, H₂ O, and brine. The organic layer was dried over Na₂SO₄, filtered and evaporated in vacuo to give 0.41 g of crude material.Flash chromatography on silica gel (5% CH₃ OH/CHCl₃, then 5-7.5% CH₃OH/CHCl₃ with 0.5% NH₄ OH) followed by precipitation from hot MeOH withEt₂ O provided 150 mg of the title Compound 93f.

mp 161°-165° C.; Mass Spec. 717 (M+H)⁺

EXAMPLE 94 Preparation of[1S-[[1R*[1R*,2S*(2S*,3R*)]]]-[2-[[3-[[3[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]-2-oxo-1-phenylethyl]carbamicacid, phenylmethyl ester (Compound 94) ##STR207##

The title Compound 94 was prepared from Compound 54 andCbz-L-phenylglycine by a procedure analogous to that used for thepreparation of Compound 55 (DMF only used along with 2 eq. N-methylmorpholine).

m.p. 203.5°-205° C.; [α]_(D) =+16.2° (c 0.22, AcOH) Elemental Analysis(%) for C₄₁ H₅₀ N₄ O₇ . 0.24 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              68.86  68.98                                                   H              7.11   7.13                                                    N              7.83   7.71                                                    ______________________________________                                    

Example 95 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-valinamide (Compound 95)##STR208##

The title Compound 95 was prepared from Compound 61 and Cbz-alanine by aprocedure analogous to that used for the two-step conversion of Compound48 to Compound 52.

EXAMPLE 96 Preparation of[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(L-alanyl)-L-valinamide, fumarate salt (Compound 96) ##STR209##

Compound 95 was converted into Compound 96 by a procedure analogous tothe one used for the synthesis of Compound 84.

mp 168°-174° C.; [α]_(D) ²² =-19° (c 0.15, CH₃ OH) High Resolution MassSpec. (FAB): C₃₃ H₅₂ N₅ O₆ =614.3908⁺ ;Δ=1.6 ppm.

EXAMPLE 97 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valinamide (Compound 97)##STR210##

The title Compound 97 was prepared from Compound 61 and Cbz-L-leucine bya procedure analogous to that used for the two-step conversion ofCompound 48 to Compound 52.

EXAMPLE 98 Preparation of[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(L-leucyl)-L-valinamide, fumarate salt (Compound 98) ##STR211##

Compound 97 was converted into Compound 98 by a procedure analogous tothe one used for the synthesis of Compound 84.

mp 184°-190° C.; [α]_(D) ²² =-12° (c 0.16, CH₃ OH) High Resolution MassSpec. (FAB): C₃₆ H₅₇ N₅ O₆ =656.4382⁺ ; Δ=0.8 ppm.

EXAMPLE 99 Preparation of[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]]bis[N²-[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]-L-valinamide] (Compound99) ##STR212##

The title Compound 99 was prepared from Compound 90 and Boc-glycine by aprocedure analogous to the one used for the synthesis of 75f.

m.p. 212°-215° C.; [α]_(D) =-26.2° (c 0.1, AcOH) Elemental Analysis (%)for C₄₄ H₆₉ N₇ O₁₀ . 0.78 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              60.74  60.81                                                   H              8.17   8.08                                                    N              11.27  11.20                                                   ______________________________________                                    

EXAMPLE 100 Preparation of[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-threoninamide (Compound 100) ##STR213##

The title Compound 100 (white solid) was prepared from Compound 54 andCbz-L-threonine by a procedure analogous to that used for the synthesisof 55 (DMF only used).

m.p. 150°-155° C.; [α]_(D) =-17.8° (C 0.18, MeOH) Mass Spec.: 679 (M+H)Elemental Analysis (%) for C₃₇ H₅₀ N₄ O₈ . 0.75 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              64.20  64.25                                                   H              7.50   7.34                                                    N              8.09   8.04                                                    ______________________________________                                    

EXAMPLE 101 Preparation of[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl) propyl]-N²-[(1H-benzimidazol-2-yl)carbonyl]-L-valinamide] (Compound 101b)

(a) Compound 101a ##STR214##

To a solution of 0.500 g (3.37 mmol) of Compound 93a in 10 mL of boilingH₂ O was added 10 drops of 3M NaOH. The resulting solution was kept at100° C. during the addition (10 min) of a solution of 0.8 g (5.05 mmol)of KMnO₄ in 50 mL of water. Heating at 100° C. was continued for 30 min.The hot mixture was filtered through celite, cooled to RT and acidifiedwith HOAc. The white precipitate was collected by suction filtration andrecrystallized from H₂ O to afford 185 mg (34%) of Compound 101a.

mp 170°-172° C. (--CO₂).

(b) Compound 101b ##STR215##

The title Compound 101b was prepared from Compounds 61 and 101a by atwo-step procedure analogous to that used for the conversion of Compound48 to Compound 52.

m.p. 210°-215° C.; [α]²⁰ _(D) =-30° (c 0.32, CH₃ OH) Mass Spec. 687(M=H)⁺ Elemental Analysis (%) C₃₈ H₅₀ N₆ O₆

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              66.45  66.53                                                   H              7.34   7.38                                                    N              12.24  12.21                                                   ______________________________________                                    

EXAMPLE 102 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N² -[phenylmethoxy)carbonyl]-L-prolinamide(Compound 102) ##STR216##

The title Compound 102 (white solid) was prepared from Compound 54 andCbz-L-proline by a procedure analogous to that used for the synthesis ofCompound 55 (used DMF only).

m.p. 142°-146° C.; [α]_(D) =-31.7° (C 0.81, MeOH) Mass Spec. 675 (M+H)Elemental Analysis (%) for C₃₈ H₅₀ N₄ O₇ . 0.69 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              66.42  66.29                                                   H              7.53   7.41                                                    N              8.15   8.28                                                    ______________________________________                                    

EXAMPLE 103 Preparation of [S-[1R*,2S*(2S*,3R*)]-N²-[3-(1H-Benzimidazol-2-yl)-1-oxo-propyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide(Compound 103b)

(a) Compound 103a ##STR217##

A mixture of σ-phenylenediamine (2.70 g, 25 mmol) and succinic acid(5.02 g, 42.5 mmol) was heated at reflux in 150 ml of 5N HCl for 3 hrs.The mixture was allowed to stand overnight at RT, filtered and then thepH was adjusted to 5 with 5N NaOH. The aqueous mixture was saturatedwith NaOAc and stored overnight at 0° C. The crude product precipitatedas a tan solid and was crystallized from H₂ O/EtOH (9:1) affording 968mg (20%) of the Compound 103a. See Chemical Abstracts CA: 19953 g(1961); French Patent 1,179,933 (May 29, 1959).

(b) Compound 103b ##STR218##

The title Compound 103b was prepared from Compounds 61 and 103a by atwo-step procedure analogous to that used for the conversion of Compound48 to Compound 52.

mp 182°-185° C.; [α]_(D) ²² =-20° (c 0.25, CH₃ OH) Analysis. calc. forC₄₀ H₅₄ N₆ O₆ . 2.5 mole H₂ O: C, 63.22; H, 7.80; N, 11.06; Found: C,63.06; H, 7.47; N, 10.90.

EXAMPLE 104 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy]-1-(phenylmethyl)propyl]-N²-[(1H-indol-2-ylmethoxy)carbonyl]-L-valinamide (Compound 104e )

(a) Compound 104a ##STR219##

A solution of LiBH₄ (1.6M in THF, 2.4 mL, 3.8 mmol) was added at -78° C.to a stirred solution of 1.0 g, 3.5 mmol, of 2-formyl-1-phenylsulfonylindole (Saulnier et al., J. Org. Chem., 47, 757 (1982)) in 30 mL of Et₂O. The mixture was allowed to come to RT and stirred for 30 min. Thereaction mixture was carefully quenched by adding sat. NaHCO₃, dilutedwith EtOAc and stirred for 30 min. The organic layer was separated,dried over MgSO₄ and concentrated to afford 0.975 g (97%) of Compound104a.

(b) Compound 104b ##STR220##

To a solution of Compound 104a (0.97 g, 3.38 mmol) in 15 mL2-methoxyethanol was added 3 mL 20% aq. KOH. The mixture was heatedunder reflux for 3 h, allowed to come to RT and partitioned betweenEtOAc and brine. The organic layer was washed with brine, dried oversodium sulfate and concentrated to afford a crude brown oil which waspurified by flash chromatography (silica gel/hexane-EtOAc 5:1 to 1:1)giving 0.45 g (91%) of Compound 104b as a yellow solid.

(c) Compound 104c ##STR221##

Trichloromethyl chloroformate (1.08 mL) was added to a stirredsuspension of L-valine methyl ester hydrochloride (3.0 g, 17.9 mmol) in10 mL dry dioxane. The mixture was refluxed for 1.5 h, concentrated, andthe residue flash distilled (bath temperature 100°-125° C., 0.5 mmvacuum) to afford 1.0 g of L-valine methyl ester isocyanate. A solutionof 0.55 g (3.5 mmol) of L-valine methyl ester isocyanate in 7.5 mL drytoluene was treated with 4M HCl in dioxane (79 mL, 0.315 mmol) at RT andstirred for 5 min. The resulting mixture was treated with 1.0 g solid K₂HPO₄ for 5 min, followed by the addition of Compound 104b (0.464 g, 3.15mmol). The mixture was refluxed for 9 h, diluted with EtOAc and washedwith sat. NaHCO₃ followed by brine. The organic phase was dried (MgSO₄),concentrated, and the crude product purified by flash chromatography(silica gel/hexane to EtOAc-hexane 1:9 to 1:4, stepwise gradient) toafford 0.51 g (53%) of Compound 104c as a yellow gummy solid.

(d) Compound 104d ##STR222##

To a solution of Compound 104c (0.5 g, 1.64 mmol) in 7 mL dioxane wasadded 0.54 M aq. LiOH (3.05 mL, 1.64 mmol), stirred at RT for 12 h,concentrated and the residue chased 3 times with toluene. The resultingoff-white Li salt (0.5 g) of the acid was used as such for the nextstep.

(e) Compound 104e ##STR223##

To a solution of Compound 104d (0.15 g, 0.51 mmol) and HOBT (0.101 g,0.66 mmol) in 1.5 mL dry DMF at 0° C. was added EDC (0.108 g, 0.56 mmol)and N-methyl morpholine (0.111 mL, 1.02 mmol), and the resulting mixturewas stirred at 0° C. for 1 h. The mixture was treated with Compound 54(0.226 g, 0.51 mmol), and stirred at RT for 12 h, concentrated, and theresidue partitioned between EtOAc and sat. NaHCO₃. The organic layer waswashed with brine, dried over MgSO₄, concentrated, and the crude productwas purified by flash chromatography (silica gel/CHCl₃ -MeOH-NH₄ OH99:1:0.5 to 90:10:1) followed by preparative HPLC (Waters Prep Nova-PackHR C18, 6 micron, 30×300 mm; eluent: MeOH-H₂ O-TFA 75:25:0.05 to80:20:0.05; UV 254 nm). The desired fractions were made basic with sat.NaHCO₃, concentrated, and the residue partitioned between EtOAc/1:1brine-sat. NaHCO₃. The organic phase was dried over MgSO₄, concentratedand the resulting white solid was triturated from 10:1 hexane-Et₂ O toafford 0.181 g (50%) of the title Compound 104e as a white solid.

[α]_(D) =+3.0° (c=0.5, CH₂ Cl₂); m.p. 115°-120° C.

High Resolution Mass Spectrum: (M+H)⁺ =716.4010, Δ 1.8 ppm error(theoretical: (M+H)⁺ : 716.5023).

EXAMPLE 105 Preparation ofS-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]-N²-(1H-benzimidazol-2-ylacetyl)-L-yalinamide (Compound 105) ##STR224##

The title Compound 105 was prepared from Compound 61 and2-benzimidazoleacetic acid (Copeland et al., J. Am. Chem. Soc., 65, 1072(1943)) by a two-step procedure analogous to that used for theconversion of Compound 48 to Compound 52.

m.p. 177°-182° C.; Mass spec (FAB) 701 (M+H)

Elemental Analysis

Calc. for C₃₉ H₅₂ N₆ O₆ ·0.78 H₂ O C, 65.52; H, 7.55; N, 11.75

Found C, 65.52; H, 7.40; N, 11.68

EXAMPLE 106 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-3-[[3-[[3,3-Dimethyl-1-oxo-2-(phenylmethoxy)butyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenyl-methyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 106e)

(a) Compound 106a ##STR225##

A solution of 1.18 g (10 mmoles) of 3,3-dimethyl-2-hydroxy-1-butanol and3.1 g of triphenylmethyl chloride in 25 ml of pyridine was stirred at RTovernight. The reaction mixture was evaporated to dryness and theresidue diluted with EtOAc and washed with 1N HCl, brine, saturatedNaHCO₃ and brine. After drying (MgSO₄), removal of solvent gave an oilyresidue which was purified by flash chromatography on a 400 cc column ofsilica gel. Elution with 5% ether-hexane afforded 3.0 g (8.5 mmoles, 85%yield) of Compound 106a as a clear colorless oil which crystallized onstanding.

(b) Compound 106b ##STR226##

To a solution of 750 mg (2.1 mmoles) of Compound 106a in 9 ml of dryTHF, at -10° C. was added dropwise 4.6 ml (2.3 moles) of 0.5M KN(TMS)₂in toluene. Cooling was removed and the clear solution stirred for 0.5hr. The reaction was ice cooled and 309 μl (2.6 mmoles) of benzylbromide was added dropwise, neat. Stirring was continued at RT for 1 hr.The reaction was diluted with brine and extracted with EtOAc. Theextracts were washed with brine, dried (MgSO₄) and the solventevaporated to yield an oily residue which was purified by flashchromatography on a 450 cc column of silica gel. Elution with 20% CH₂Cl₂ -hexane gave 880 mg (1.95 mmoles, 94% yield) of Compound 106b as acolorless oil.

(c) Compound 106c ##STR227##

A solution of 0.8 g (1.8 mmoles) of Compound 106b and 40 mg ofp-toluenesulfonic acid in 20 ml of MeOH was stirred at RT for 3 hr. Thereaction was evaporated to dryness and the residue placed on a 400 cccolumn of silica gel. Elution with 20% Et₂ O-hexane, followed by 30% Et₂O-hexane gave 233 mg (1.12 mmole, 63%) of Compound 106c as a clearcolorless oil.

(d) Compound 106d ##STR228##

To a solution of 5.8 g (16.8 mmoles) of pyridinium dichromate in 8 ml ofDMF at RT was added dropwise a solution of 1.0 g (4.8 mmoles) ofCompound 106c in 2 ml of DMF. The dark solution was stirred overnight,poured into 80 ml of ice/water and extracted with Et₂ O. The extractswere filtered through a Celite-MgSO₄ mixture and extracted withsaturated NaHCO₃, and H₂ O. The combined aqueous fractions were washedonce with Et₂ O, acidified with 6N HCl, and extracted with Et₂ O. Thecombined extracts were washed with brine, dried (MgSO₄) and the solventremoved to yield 480 mg of clear colorless oil. Distillation (kugelrohr,140° C., 0.05 mm) gave 410 mg (1.8 mmoles, 38%) of Compound 106d as aclear colorless oil.

(e) Compound 106e ##STR229##

The title Compound 106e was prepared as a white solid from Compounds 54and 106d by a procedure analogous to that used for the synthesis ofCompound 55 (DMF only; 2 eq. of N-methylmorpholine used).

m.p. 114°-117° C.; Mass spec. (M+H) 648

Elemental Analysis

Calc. for C₃₈ H₅₃ N₃ O₆ : C, 70.45; H, 8.25; N, 6.49

Found: C, 70.09; H, 8.27; N, 6.57

EXAMPLE 107. Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, phenylmethyl ester (Compound 107) ##STR230##

Compound 45 was converted to the title Compound 107 by a procedureanalogous to the one used for the synthesis of Compound 39.

¹ H NMR (CD₃ OD): δ1.23 (m, 9H), 2.42 (m, 1H), 2.59 (m, 1H), 2.91 (m,1H), 3.07 (m, 1H), 3.18 (m, 1H), 3.28 (m, 1H), 3.44-3.88 (m's, 6H), 4.27(m, 1H), 4.52 (m, 2H), 4.87 (m, 2H), 7.05-7.47 (m's, 19H), 7.64 (m, 2H),7.78 (m, 2H).

EXAMPLE 108 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)-[(9H-fluoren-9-yl-methoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 108) ##STR231##

Compound 107 was converted to the title Compound 108 by a procedureanalogous to that used for the synthesis of Compound 61 (EtOH wasemployed in place of MeOH). Compound 108 was used without furtherpurification in the preparation of Compound 109 following.

EXAMPLE 109 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)carbonyl]-amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-valinamide (Compound 109) ##STR232##

Compound 108 was coupled with Cbz-valine by a procedure analogous tothat used for the preparation of Compound 51 to give the title Compound109.

Mass Spec. (FAB): 899 (M+H)⁺.

EXAMPLE 110 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)-[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-valinamide, monohydrochloride (Compound110) ##STR233##

Acetyl chloride (39.8 uL, 56.0 mmol, 10 eq.) was added at 0° C. to MeOH(560 uL) followed by Compound 109 (50 mg, 0.56 mmol). The viscoussolution was diluted with 1 mL MeOH and an additional solution of acetylchloride (39.8 uL) in MeOH (2 mL) was added. The white turbid mixturewas allowed to warm to RT, stirred for 4 hrs, and then gently warmed to40° C. After 1 h, the volatiles were removed in vacuo to yield 46 mg(99%) of Compound 110 which was used without further purification.

EXAMPLE 111 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[[N-[(phenylmethoxy)-carbonyl]-L-valyl]amino]butyl][(9H-fluoren-9 -yl-methoxy)carbonyl]amino]-1-(phenylmethyl)propyl]-N²⁻[(phenylmethoxy)carbonyl]-L-asparaginamide (Compound 111) ##STR234##

Compound 110 and Cbz-L-asparagine were reacted by a procedure analogousto that used for the preparation of Compound 51 to give the titleCompound 111.

Mass Spec.: (FAB): 1047.5 (M+H)⁺.

EXAMPLE 112 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[[N-[(phenylmethoxy)carbonyl]-L-valyl]amino]butyl]amino]-1-(phenylmethyl)propyl]-N²[(phenylmethoxy)-carbonyl]-L-asparaginamide, monohydrochloride (Compound112) ##STR235##

Compound 111 was converted to the title Compound 112 by a procedureanalogous to that used for the synthesis of Compound 42. Compound 112was isolated as the HCl salt which was recrystallized from MeOH/Et₂ O.

mp 198°-200° C.; [α]_(D) =-31° (c 0.2, AcOH) .

Mass Spec.: (FAB): 825 (M+H)⁺.

Analysis calculated for C₄₅ H₅₆ N₆ O₉.HCl.2.30H₂ O: C, 59.93; H, 6.77;N, 9.32;

Found: C, 60.26; H, 6.56; N, 8.99;

EXAMPLE 113 Preparation of[1S-[1R*,2S*(2R*,3R*)]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, phenylmethyl ester (Compound 113c)

(a) Compound 113a ##STR236##

Compound 113a was prepared during the reduction procedure in whichCompound 44a above was prepared and isolated.

(b) Compound 113b ##STR237##

Compound 113b was prepared from Compound 113a by a procedure analogousto that used for the synthesis of Compound 1b(ii).

(c) Compound 113c ##STR238##

Compounds 113b and 16b (1 eq. of each) were reacted by a procedureanalogous to that used for the synthesis of Compound 4b to give thetitle Compound 113c (white solid).

¹ H NMR (CD₃ OD): δ1.29 (s, 9H), 2.56 (dd, J=10.5, 14 Hz, 1H), 2.66 (m,2H), 2.80 (m, 3H), 2.91 (dd, J=5.5, 13.5 Hz, 1H), 3.09 (dd, J=3.5, 14Hz, 1H), 3.60 (m, 2H), 3.80 (m, 1H), 3.86 (m, 1H), 4.99 (m, 2H), 7.20(m, 15H).

EXAMPLE 114 Preparation of[1S-[1R*,2S*(2R*,3R*)]-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 114) ##STR239##

Compound 113c was converted to the title Compound 114 (white foam) usingconditions analogous to those used for the synthesis of Compound 7.

¹ H NMR (CD₃ OD): δ1.29 (s, 9H), 2.54 (dd, J=10.5, 14 Hz, 1H), 2.63 (dd,J=7.5, 12 Hz, 1H), 2.71 (m, 2H), 2.85 (dd, J=9.5, 12.5 Hz, 1H), 2.91 (m,2H), 3.10 (m, 2H), 3.62 (m, 3H), 7.28 (m, 10H).

EXAMPLE 115 Preparation of[S-[1R*,2R*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-phenylmethyl)propyl]-N²-[(phenylmethoxy)-carbonyl]-L-valinamide (Compound 115) ##STR240##

Compound 114 and Cbz-valine were reacted by a procedure analogous tothat used for the synthesis of Compound 55 (DMF only as solvent) to givethe title Compound 115.

mp 183°-186° C.; [α]_(D) =-38.7° (c 0.23, MeOH).

Mass Spec. FAB: M+H=677.

Analysis calc. for C₃₈ H₅₂ N₄ O₇ ·0.81 H₂ O: C, 66.01; H, 7.82; N, 8.10;

Found C, 65.95; H, 7272; N, 8.16.

EXAMPLE 116 Preparation of[S-(R*,R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamicacid, 1,1-dimethylethyl phenylmethyl ester (Compound 116) ##STR241##

Compounds 27a and 113b (1 eq. of each) were reacted by a procedureanalogous to that used for the synthesis of Compound 4b to give thetitle Compound 116 (white foam).

¹ H NMR (CD₃ OD): δ1.34 (s, 9H), 2.52 (m, 4H), 2.75 (m, 2H), 2.87 (m,2H), 3.69 (m, 3H), 3.82 (m, 1H), 4.98 (s, 2H), 7.22 (m, 15H).

EXAMPLE 117 Preparation of[S-[1R*,2R*(2R*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)-carbonyl]-L-valinamide (Compound 117) ##STR242##

Compound 116 was converted to the title Compound 117 by a two-stepprocedure analogous to that used for the synthesis of Compound 115(removal of the Cbz group using conditions analogous to those forCompound 7, and coupling of the resulting product with Cbz-valineanalogous to Compound 55 [DMF only]).

mp 170°-175° C.; [α]_(D) =-51.5° (c 0.20, MeOH).

Mass Spec. FAB+ions: M+H=677.

Analysis calc. for C₃₈ H₅₂ N₄ O₇ ·0.59 H₂ O: C, 66.38; H, 7.80; N, 8.15;

Found C, 66.25; H, 7.61; N, 8.28.

EXAMPLE 118 Preparation of[S-(R*,R*)]-1,1'-Iminobis(3-amino-4-phenyl-2-butanol) (Compound 118)##STR243##

Compound 3 was converted to the title Compound 118 (which was usedwithout further purification in the following Example as the tri-HClsalt) by a procedure analogous to that used for the synthesis ofCompound 32. R_(f) =0.035 (20:2:78 MeOH:NH₄ OH:CHCl₃).

EXAMPLE 119 Preparation of[S-(1R*,2R*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[N²-[phenylmethyloxy)carbonyl]-L-valinamide] (Compound 119) ##STR244##

Compound 118 and Cbz-L-valine were reacted by a procedure analogous tothat used for the synthesis of Compound 75f to give the title Compound119.

m.p. dec. 206°-208° C.; [α]_(D) ²⁵ =-42.8° (c 0.14, DMSO).

MS: (FAB): 810 (M+H).

Anal. Calc. for C₄₆ H₅₉ N₅ O₈ ·1.08 H₂ O: C, 66.62; H, 7.43; N, 8.44

Found: C, 66.71; H, 7.33; N, 8.35

EXAMPLE 120 Preparation of [S-[1R*,2S*(2S*,3R*)]]-N-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)amino]-2-hydroxy-1-(phenylmethyl)-propyl]-N²-[(phenylmethoxy)carbonyl]-L-valinamide (Compound 120) ##STR245##

Compound 52 was converted to the title Compound 120 (used withoutfurther purification in the next Example) by a procedure analogous tothat used for the synthesis of Compound 110.

¹ H NMR (CD₃ OD): δ0.52 (d, J=6.6 Hz, 3H), 0.56 (d, J=6.6 Hz, 3H), 1.70(m, 1H), 2.70 (m, 1H), 2.95 (m, 1H), 3.05 (m, 4H), 3.17 (m, 2H), 3.57(d, J=7.2 Hz, 1H), 3.72 (m, 1H), 3.80 (m, 1H), 4.07 (m, 1H), 4.28 (m,1H), 5.11 (s, 2H), 7.12-7.42 (m's, 15H).

EXAMPLE 121 Preparation of [S-[1R*,2S*(2S*,3R*)]]-N²-[(1,1-Dimethylethoxy)carbonyl]-N-[2-hydroxy-3-[[2-hydroxy-4-phenyl-3-[[N-[(phenylmethoxy)carbonyl]-L-valyl]amino]butyl]amino]-1-(phenylmethyl)propyl]-L-asparacinamide(Compound 121) ##STR246##

Compound 120 was reacted with Boc-L-asparagine by a procedure analogousto that used for the synthesis of Compound 55 (DMF only; 2 eq. ofN-methylmorpholine added) to give the title Compound 121.

mp 199°-202° C.; [α]_(D) =-31° (c 0.2, AcOH).

Mass Spec.: FAB (M+H)⁺ 791.

Analysis calculated for C₄₂ H₅₈ N₆ O₉.0.61H₂ O: C, 62.90; H, 7.44; N,10.48;

Found: C, 63.04; H, 7.33; N, 10.34.

EXAMPLE 122 Preparation of [R-(R*,S*)]-[[(Phenylmethyl)-imino]bis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamic acid, bis(1-methylethylester (Compound 122) ##STR247##

To a solution of Compound 32 (165 mg; 0.35 mmol) and 0.27 mL (1.56 mmol)of i-Pr₂ NEt in 0.35 mL of dry DMF at 0° C. was added 0.78 mL (0.78mmol) of isopropyl chloroformate. The reaction mixture was stirred at RTfor 72 h, at which point it was quenched with saturated aqueous NaHCO₃and extracted with Et₂ O. The organic layer was washed with brine anddried (Na₂ SO₄). The salts were filtered and the solvents removed invacuo to give a residue, which was purified on silica gel (gradient of75:25 to 50:50 hexane:EtOAc) to give 100 mg of Compound 122 (whitesolid).

¹ H NMR (CDCl₃): δ1.11 (d, 6H), 1.70 (1H), 1.17 (d, 6H), 2.50-2.59 (m,4H), 2.70-2.83 (m, 4H), 3.40-3.51 (m, 2H), 3.60-3.83 (m, 5H), 4.69 (m,2H), 4.76-4.82 (m, 2H), 7.13-7.35 (m, 15H).

EXAMPLE 123 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propandiyl]biscarbamicacid, bis(1-methylethyl)ester (Compound 123) ##STR248##

Compound 122 was converted to the title Compound 123 by a procedureanalogous to that used for the synthesis of Compound 2.

m.p. 195°-200° C.; [α]_(D) =-13.2° (c, 0.09, MeOH)

Mass spec. (CI) (M+H) 516

Elemental Analysis (%)

C₂₈ H₄₁ N₃ O₆ ·0.63 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              65.22  64.00                                                   H              8.01   7.88                                                    N              8.15   7.80                                                    ______________________________________                                    

EXAMPLE 124 Preparation of[1S-[1R*,2R*(2S*,3R*)]]-[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenvlbutvl]amino]-2-hydroxy-1-(phenyl-methyl)propyl]carbamicacid, phenylmethyl ester (Compound 124) ##STR249##

Compounds 27a and 44a (1 eq. of each) were reacted by a procedureanalogous to that used for the synthesis of Compound 4b (white powder)to give the title Compound 124.

¹ H NMR (DMSO-d⁶): δ1.30 (s, 9H), 2.57 (m, 6H), 2.80 (dd, J=5.5, 13.5,1H), 3.01 (d, J=11 Hz, 1H), 3.41 (m, 1H), 3.50 (m, 1H), 3.60 (m, 1H),3.70 (m, 1H), 4.73 (m, 1H), 4.85 (m, 1H), 4.88 (d, J=13 Hz, 1H), 4.93(d, J=13 Hz, 2H), 6.40 (d, J=9 Hz, 1H), 7.27 (m, 15H).

EXAMPLE 125 Preparation of[S-[1R*,2S*(2R*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²[(phenylmethoxy)carbonyl]-L-valinamide (Compound 125) ##STR250##

Compound 124 was converted to the title Compound 125 by a two-stepprocedure analogous to that used for the synthesis of Compound 115(removal of Cbz group using conditions analogous to those used forCompound 7 (AcOH used in place of MeOH), and coupling of the resultingproduct with Cbz-valine analogous to Compound 55 (DMF only).

mp 175°-180° C.; [α]_(D) =-26.0° (c 0.15, MeOH).

Mass Spec. FAB+ions: M+H=677.

Analysis calc. for C₃₈ H₅₂ N₄ O₇ ·0.95 H₂ O: C, 65.77; H, 7.83; N, 8.07;

Found C, 65.55; H, 7.59; N, 8.29.

EXAMPLE 126 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,3-Dimethylbutyl)amino]-2-hydroxy-4-phenylbutyl][[2-(trimethylsilyl)ethoxy]carbonyl]-amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 126) ##STR251##

To a solution of Compound 48 (300 mg, 0.51 mmol) in 1.55 mL MeOH(adjusted to pH 6 with AcOH) was added 3,3-dimethylbutylraldehyde (70μl, 0.56 mmol, 1.1 eq. ) and a small amount of pulverized 4 Å molecularsieves. To this mixture at RT was added NaCNBH₃ (48 mg, 0.77 mmol) intwo portions. The reaction was quenched after 2 h with 10 mL saturatedNaHCO₃ solution and extracted with CH₂ Cl₂. The combined extracts werewashed with brine, dried over MgSO₄, filtered, concentrated, and driedin vacuo to yield 330 mg crude oil. The residue was purified bychromatography on a 3×16 cm silica gel column, eluting with CH₂ Cl₂,then 98.9:1:0.1 and 97.8:2:0.2 CH₂ Cl₂ :MeOH:NH₄ OH to afford 238 mg(69%) of Compound 126.

Mass Spec: 672 (M+H)⁺

EXAMPLE 127 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3.3-Dimethylbutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 127) ##STR252##

Compound 126 was converted to the title Compound 127 by a procedureanalogous to the one used for the synthesis of Compound 21.

mp 89°-91° C.; [α]_(D) =+9° (c 0.24, MeOH).

Mass Spec: Fab (M+H)⁺ : 528. C, 68.82; H, 9.40; N, 7.77;

Found: C, 68.51; H, 9.16; N, 8.02.

EXAMPLE 128 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-Amino-2-hydroxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, monoacetate salt (Compound 128)##STR253##

A solution of 1.69 g (2.1 mmoles) of Compound 107 and 2.0 ml of1,4-cyclohexadiene in 60 ml of EtOH containing 225 mg of 10% Pd/Ccatalyst was stirred under a hydrogen atmosphere for 3.5 hr. Thecatalyst was removed by filtration through Celite and 0.5 ml of HOAcadded. Evaporation to dryness gave 1.8 g (assumed 100% yield) ofCompound 128 as a white solid. [TLC: R_(f) =0.38, 10% MeOH-CH2Cl₂ ].

Mass Spec. 666 (M+H).

EXAMPLE 129 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[(9H-Fluoren-9-ylmethoxy)carbonyl][3-(formylamino)-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 129) ##STR254##

Formic acetic anhydride was prepared by the addition of 260 μl of formicacid to 745 μl of acetic anhydride at 0° C. and the resulting solutionthen heated at 50° C. for 2 h. The anhydride was dissolved in 5 ml ofTHF and added to a slurry of 1.8 g (assumed 2.1 mmoles) of Compound 128in 20 ml of THF. The reaction was stirred at 0° C. for 30 min, then atRT for 30 min, and then evaporated to dryness to yield the crude productas a white foam. This material was purified by flash chromatography on a75 cc column of silica gel. Elution with 50% EtOAc-hexane, followed by100% EtOAc gave 1.16 g (1.67 mmole, 80% yield over two steps) ofCompound 129 as a solid white foam. [TLC: R_(f) =0.29, EtOAc]

Mass Spec. 694 (M+H).

EXAMPLE 130 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[(9H-Fluoren-9-ylmethoxy)carbonyl][2-hydroxy-3-(methylamino)-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, monoacetate salt (Compound 130)##STR255##

To a solution of 785 mg (1.13 mmoles) of Compound 129 in 10 ml of THF at0° C. was added dropwise 2.85 ml of 2M borane-methyl sulfide in THF.After foaming ceased the reaction mixture was heated at 50° C. for 1 hthen cooled to 0° C. and excess borane hydrolyzed by the dropwiseaddition of approx. 10 ml of MeOH. After reaction ceased, 0.5 ml of HOAcwas added and the solution heated at 50° C. for 6 h to destroy theamine-boron complex. The solution was evaporated to dryness and theresidue purified by flash chromatography on a 35 cc column of silica gel(elution with 100% EtOAc, 10% MeOH-EtOAc, and 20% MeOH-EtOAc). After theappropriate fractions were combined, 0.5 ml of HOAc was added and thesolvent removed to yield 625 mg (0.84 mmole, 75% yield) of Compound 130as a solid white foam. This material contained approximatly 3equivalents of HOAc by ¹ H NMR. [TLC: R_(f) =0.43, 10% MeOH-CH₂ Cl₂ ].

Mass Spec. 690 (M+H).

EXAMPLE 131 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)-carbonyl]amino]-2-hydroxy-1-(phenyl-methyl)propyl]methylcarbamicacid, 1,1-dimethylethyl ester (Compound 131) ##STR256##

To a solution of 160 mg (0.166 mmole, based on 3 eq of HOAc) of Compound130 and 137 mg (0.63 mmole) of di-t-butyl dicarbonate in 1 ml of DMF at0° C. was added, dropwise, 146 μl of Et₃ N. After 30 min an additional65 mg of di-t-butyl dicarbonate and 75 μl of Et₃ N were added andstirring continued for an additional 30 min. The reaction was dilutedwith EtOAc and washed with water and brine, dried (MgSO₄), and thesolvent removed to yield a residue which was purified by flashchromatography on a 20 cc column of silica gel (elution with 25%EtOAc/hexane, followed by 50% EtOAc/hexane) to give 129 mg (0.166 mmole,89% yield) of Compound 131 as a solid white foam. [TLC: R_(f) =0.30, 50%EtOAc/Hexane]

Mass Spec. 780 (M+H).

EXAMPLE 132 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-3-[[-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]methylcarbamicacid, 1,1-dimethylethyl ester (Compound 132) ##STR257##

Compound 131 was converted to the title Compound 132 by a procedureanalogous to the procedure used for the synthesis of Compound 42 (CH₂Cl₂ used in place of DMF).

[α]_(D) =-19.6° (c=0.6, MeOH); MS: (M+H)⁺ =558; MW=557 Anal. Calc. forC₃₁ H₄₇ N₃ O₆ ·0.33 H₂ O: C, 66.06; H, 8.52; N, 7.46. Found: C, 66.00;H, 8.47; N, 7.52.

EXAMPLE 133 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N-methyl-N²-[(phenylmethoxy)carbonyl]-L-valinamide (Compound 133) ##STR258##

To a solution of 75 mg (0.087 mmole) of Compound 130 in 0.5 ml of MeOHwas added a solution of 6.2 μl (0.087 mmole) of AcCl in 1 ml of MeOH.The solution was evaporated to dryness and the residue co-evaporatedfrom toluene to remove traces of HOAc. The residue was dried under highvacumn for 2 h to give 68 mg of the hydrochloride salt as a white solid.This material was diluted with 1 ml of CH₂ Cl₂, cooled to 0° C. and 44mg (0.174 moles) Cbz-L-valine and 49 mg (0.192 mmole) of BOP-Cl added assolids, followed by 46 μl (0.261 mmole) of i-Pr₂ NEt. The solution wasstirred at 0° C. for 4.5 hr and then placed directly on a 16 cc columnof silica gel (elution with 50% EtOAc/hexane afforded 70 mg (0.077mmole, 88% yield) of the title Compound 133 as a white foam. [TLC: R_(f)=0.27, 50% EtOAc-hexane].

Mass Spec.: 913 (M+H).

EXAMPLE 134 Preparation of[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]-N-methyl-N.sup.2-[(phenylmethoxy)carbonyl]-L-valinamide (Compound 134) ##STR259##

Compound 133 was converted to the title Compound 134 (solid white foam)by a procedure analogous to the procedure used for the synthesis ofCompound 42 (CH₂ Cl₂ used in place of DMF).

[α]_(D) =-35.6° (c 0.82, MeOH).

Mass Spec.: 691 (M+H).

Elemental Analysis (%)

for C₃₉ H₅₄ N₄ O₇ ·0.36 H₂ O C; 67.18; H; 7.91; N; 8.03

Found: C; 67.12; H; 7.83; N; 8.09

EXAMPLE 135 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)amino]-carbonyl]methylamino]-2-hydroxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)-carbonyl]amino]-2-hydroxy-1(phenylmethyl)propyl]-carbamicacid, 1,1-dimethylethyl ester (Compound 135) ##STR260##

A solution of 110 mg of Compound 130 (0.13 mmole, material contained 3eq. of HOAc by NMR) and 14.5 μl (0.16 mmole) of t-butyl isocyanate in 2ml of CH₂ Cl₂ was stirred at RT for 3 hr. An additional 7 μl of t-butylisocyanate was added and stirring continued for 2.5 hr. The solution wasevaporated to dryness to give 112 mg of a white foam which was combinedwith material from a similar reaction (total 130 mg) and purified byflash chromatography on a 20 cc column of silica gel (elution with 50%EtOAc/hexane) to afford 110 mg (0.14 mmole, 88% yield) of the titleCompound 135 as a solid white foam. [TLC: R_(f) =0.66, 100% EtOAc].

Mass Spec. 799 (M+H).

EXAMPLE 136 Preparation of[1S-[1R*,2S*(2S,3R*)]]-[3-[[3-[[(1,1-Dimethylethyl)amino]carbonyl]methylamino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl))propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 136) ##STR261##

Compound 135 was converted to the title Compound 136 (solid white foam)by a procedure analogous to the procedure used for the synthesis ofCompound 42 (CH₂ Cl₂ used in place of DMF). TLC: R_(f) =0.31, CH₂ Cl₂-MeOH-NH₄ OH, 90:10:1]

[α]_(D) =-15.2° (c=0.27, MeOH)

Mass Spec.: 557 (M+H) .

Calc. for C₃₁ H₄₈ N₄ O₅ ·0.28 H₂ O (561.79): C,66.28; H, 8.71, N, 9.97.

Found: C, 66.40; H, 8.59, N, 9.85.

EXAMPLE 137 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)amino]thioxomethyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy1-(phenylmethyl))propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 137) ##STR262##

Compound 48 was converted to the title Compound 137 (white solid) by atwo-step procedure analogous to that used for the preparation ofCompound 50 (t-butylisothiocyanate used in place of t-butylisocyanate).

m.p. 85°-87° C. ("softening" at 75°-85° C.).

[α]_(D) =-12.8° (c=0.40, MeOH)

Compound 138 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propandiyl]]biscarbamicacid, bis(1,1-dimethylpropyl)ester (Compound 138b)

(a) Compound 138a ##STR263##

Compound 138a was obtained as a white solid by reaction of Compound 32with di-tertamyldicarbonate using conditions analogous to those used forthe synthesis of Compound 131 (i-Pr₂ NEt used instead of Et₃ N).

Mass Spec. 662 (M+H)

(b) Compound 138b ##STR264##

Compound 138a was converted to Compound 138b (white solid) by aprocedure analogous to that used for the preparation of Compound 2.

m.p. 161°-163° C.; [α]_(D) =+147° (c=0.2, CH₂ Cl₂)

Elemental Analysis (%)

for C₃₂ H₄₉ N₃ O₆ ·0.52 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              66.13  66.42                                                   H              8.68   8.73                                                    N              7.23   6.94                                                    ______________________________________                                    

EXAMPLE 139 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, bis(2,2-dimethylpropyl)ester (Compound 139) ##STR265##

Compound 139 was obtained as a solid by reaction of Compound 32withneopentyl chloroformate (J. Org. Chem. 49, 1174 (1984)), and subsequentdeprotection analogous to the two step procedure used for the synthesisof Compound 123.

m.p. 152°-154° C.; [α]²⁰ _(D) =-12.5° (c=0.1, CH₃ OH)

TLC:Rf=0.43 (silica gel); Solvent:90:9:1

CH₂ Cl₂ :MeOH:NH₄ OH.

EXAMPLE 140 Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-(5,5-Dimethyl-2-oxo-3-oxazolidinyl)-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 140f)

(a) Compound 140a ##STR266##

To a solution of the Cbz-intermediate formed during the first step ofthe synthesis of Compound 48 (100 mg, 0.138 mmol) in dry CH₂ Cl₂ (1 mL)at 0° C. was added ethyl vinyl ether (300 μL, 3.14 mmol), followed bypyridinum p-toluene sulfonate (10.7 mg, 0.042 mmol) and the reactionstirred at RT for 18 h. The reaction mixture was diluted with EtOAc andwashed with saturated NaHCO₃. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo to yield a gummy white solidwhich was purified by silica gel chromatography, eluting with EtOAc (10to 40%)/hexane to afford 105 mg of Compound 140a (88% yield) as a whiteresidue. TLC (silica gel/Hexanes:EtOAc 1:1): R_(f) =0.7

(b) Compound 140b ##STR267##

Compound 140a was converted to Compound 140b (colorless oil) by aprocedure analogous to that used for the synthesis of Compound 54.

Mass Spec.: 732 (M+H)

(c) Compound 140c ##STR268##

To a solution of Compound 140b (175 mg, 0.24 mol) in EtOH (2 mL) in apressure tube was added isobutylene oxide (0.66 mL, 7.17 mmol) and thetube sealed under argon and heated at 110° C. for 4 h, and then at 150°C. for 2 h. The solvents were removed in vacuo, and the oily residuepurified by silica gel chromatography, eluting with CH₃ OH (1 to10%)/CHCl₃ to give 138 mg of Compound 140c (71% yield) as a colorlessgummy residue.

Mass Spec. 805 (M+H)

(d) Compound 140d ##STR269##

To a solution of Compound 140c (103 mg, 0.13 mmol) in dry CH₂ Cl₂ (375μL) at 0° C. was added pyridine (125 μL, 1.54 mmol), followed by 20%COCl₂ in toluene (166 μL, 1.93 M) and the mixture stirred at 0° C. for25 min. The reaction mixture was quenched with saturated NaHCO₃,extracted with EtOAc, the organic phase dried (MgSO₄), filtered andconcentrated in vacuo to afford 98 mg of Compound 140d (ca. 91% crudeyield) as yellow foamy residue.

TLC (silica gel/CHCl₃ : MeOH 98:2 ): R_(f) =0.26

(e) Compound 140e ##STR270##

To a solution of Compound 140d (98 mg, 0.12 mmol) in 1.5 mL acetone wasadded pyridinum p-toluene sulfonate (98 mg, 0.12 mmol) and the yellowsolution stirred at RT for 18 h. The solvent was removed and the residuetaken into EtOAc (10 mL) and washed with saturated NaHCO₃. The organicextracts were dried (anhydrous Na₂ SO₄), filtered and concentrated todryness.: The crude product was purified by silica gel chromatography,eluting with CH₃ OH (1 to 10%)/CHCl₃ to afford 68 mg of Compound 140e(81% yield) as a yellow residue.

Mass Spec. 686 (M+H)

(f) Compound 140f ##STR271##

Compound 140e was converted to the title Compound 140f (yellow solid) bya procedure analogous to that used for the synthesis of Compound 21.

m.p. 55°-58° C., [α]_(D) =-3.96° (c=0.2, CH₂ Cl₂).

Analysis for: C₃₀ H₄₃ N₃ O₆ ·2.19 H₂ O

Calculated: C, 62.00; H, 8.22; N, 7.23;

Found: C, 62.25; H, 7.63; N, 6.98.

EXAMPLE 141 Preparation of [S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]methylamino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)-carbonyl]-L-valinamide] (Compound 141e )

(a) Compound 141a ##STR272##

Compound 129 was converted to Compound 141a (yellow solid) by aprocedure analogous to that used for the synthesis of Compound 32.

(b) Compound 141b ##STR273##

Compound 141a was converted to Compound 141b (white solid) by aprocedure analogous to that used for the synthesis of Compound 51 (CH₂Cl₂ was used as solvent). TLC: R_(f) =0.21, 100% EtOAc.

(c) Compound 141c ##STR274##

Compound 141b was converted to Compound 141c (white foam) by a procedureanalogous to that used for the synthesis of Compound 130. TLC: R_(f)=0.42, CH₂ Cl₂ -MeOH-NH₄ OH, 90:10:1.

(d) Compound 141d ##STR275##

Compound 141c was converted to Compound 141d (white foam) by a procedureanalogous to that used for the synthesis of Compound 131.

(e) Compound 141e ##STR276##

Compound 141d was converted to Compound 141e (white foam) by a procedureanalogous to that used for the synthesis of Compound 42. TLC: Rf =0.38,CH₂ Cl₂ :MeOH:NH₄ OH, 90:10:0.1 (UV detection).

[α]_(D) =-27.9° (c 0.72, MeOH)

Elemental Analysis (%)

C₃₉ H₅₄ N₄ O₇

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              67.80  67.51                                                   H              7.88   7.94                                                    N              8.11   8.14                                                    ______________________________________                                    

EXAMPLE 142 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[9-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-methoxy-1-(phenylmethyl)propyl]carbamicacid 1,1-dimethyl-ethyl ester (Compound 142d)

(a) Compound 142a ##STR277##

A solution of 300 mg (1.14 mmole) of Compound 1b(i), 186 mg (2.85mmoles) of NaN₃ and 111 mg (2.05 mmoles) of NH₄ Cl in 6 ml of MeOH wasstirred at reflux overnight. The white solid residue obtained on removalof solvent was dissolved in EtOAc and washed with H₂ O and brine. Drying(MgSO₄) and concentration gave 300 mg (0.98 mmole, 86%) of Compound 142aas a white solid. TLC: R_(f) =0.21, 25% EtOAc-hexane.

(b) Compound 142b ##STR278##

To a suspension of 48 mg (1.2 mmoles) of 60% NaH (hexane washed) in 1 mlof dry THF at RT was added a solution of 295 mg (0.96 mmole) of Compound142a in 4 ml of THF. The reaction was stirred for 2 hr at which time 89μl (1.44 moles) of methyl iodide was added. Stirring was continued for 1hr then the reaction was diluted with EtOAc and washed with H₂ O, 10%Na₂ S₂ O₃, and brine. After drying (MgSO₄), removal of solvent gave awhite solid residue which was purified by flash chromatography on a 130cc column of silica gel (elution with 20% EtOAc/hexane) to give 206 mg(0.64 mmole, 67%) of Compound 142b as a white solid. TLC: R_(f) =0.55,25% EtOAc-hexane.

(c) Compound 142c ##STR279##

A solution of 150 mg (0.47 mmole) of Compound 142b in 3 ml of MeOHcontaining 45 mg of 10% Pd/C was hydrogenated at RT for 1.5 hr(balloon). The reaction was diluted with additional MeOH, 0.5 ml of NH₄OH was added, and stirring was continued for 15 min. The catalyst wasremoved by filtration through Celite (MeOH wash) and the filtrateconcentrated. The residue was taken up in CH₂ Cl₂, dried (MgSO₄), andthe solvent evaporated to afford 122 mg (0.41 mmole, 88%) of Compound142c as a white solid. TLC: R_(f) =0.28, CH₂ Cl₂ :MeOH:NH₄ OH,(90:10:1).

(d) Compound 142d ##STR280##

Compounds 142c and 1b(i) were reacted by a procedure analogous to thatused for the synthesis of Compound 4b to give the title Compound 142d(white foam). TLC: Rf=0.37, CH₂ Cl₂ :MeOH:NH₄ OH, 90:10:0.1

[α]_(D) =-3.9° (c 0.67, MeOH)

Elemental Analysis (%)

C₃₁ H₄₇ N₃ O₆ ·0.78 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              65.11  64.75                                                   H              8.56   8.22                                                    N              7.35   7.71                                                    ______________________________________                                    

EXAMPLE 143 Preparation of[1S-[1R*,2S*)]-[[[[2-(Trimethylsilyl)ethoxy]carbonyl]imino]bis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamicacid, 1,1-dimethylethyl2,3-dihydro-1H-inden-1-yl ester (Compound 143)##STR281##

To a solution of 53 mg (0.0924 mmol) of Compound 48 in 200 μL of CH₃ CNat RT were added 29 mg of Compound 67a and 26 μL of Et₃ N. After 22 h,an additional 3 mg of Compound 67a and 5 μL of Et₃ N were added to thereaction mixture. After 48 h, the mixture was diluted with 50 mL of CH₂Cl₂ and washed with 10% citric acid and saturated NaHCO₃. The organiclayer was dried over Na₂ SO₄, filtered and concentrated in vacuo. Flashchromatography on silica gel eluting with 10-50% EtOAc-hexane provided57 mg (84%) of Compound 143.

EXAMPLE 144 Preparation of[1S-(1R*,2S)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]-bis[carbamicacid], 1,1-dimethylethyl-2,3-dihydro-1H-inden-1-yl ester Compound 144)##STR282##

Compound 143 was converted to the title Compound 144 by a procedureanalogous to that used for the synthesis of Compound 21. (1:1 mixtureR:S at *)

mp 157°-166° C.; [α]²⁰ _(D) =-11° (c=0.35, CH₃ OH)

Mass Spec. 604 (M+H)⁺

Elemental Analysis (%)

C₃₅ H₄₅ N₃ O₆ ·0.71 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              68.18  68.40                                                   H              7.59   7.55                                                    N              6.81   6.59                                                    ______________________________________                                    

EXAMPLE 145 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-dimethylethyl(R)-2,3-dihydro-1H-inden-1-yl ester (Compound145) ##STR283##

Compound 48 was converted to the title Compound 145 by a two-stepprocedure analogous to that used for the synthesis of Compound 144except that the p-nitrophenyl carbonate of R-(-)-indanol was used.

mp 187°-190° C.; [α]²⁰ _(D) =-4.9° (c=0.35, DMSO)

Mass Spec. 604 (M+H)⁺

Elemental Analysis (%)

C₃₅ H₄₅ N₃ O₆ +0.51 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              68.58  68.24                                                   H              7.57   7.29                                                    N              6.86   7.20                                                    ______________________________________                                    

EXAMPLE 146 Preparation of [1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-dimethylethyl(S)-2,3-dihydro-1H-inden-1-yl ester (Compound146) ##STR284##

Compound 48 was converted to the title Compound 146 by a two-stepprocedure analogous to that used for the synthesis of Compound 144except that the p-nitrophenyl carbonate of S-(+)-indanol was used.

mp 175°-178° C.; [α]²⁰ _(D) =-26° (c=0.12, CH₃ OH)

Mass Spec. 604 (M+H)⁺

Elemental Analysis (%)

C₃₅ H₄₅ N₃ O₆ ·0.25 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              69.12  68.96                                                   H              7.54   7.62                                                    N              6.91   7.07                                                    ______________________________________                                    

EXAMPLE 147 Preparation of[1S-(1R*,2S*)]-[[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl2,3-dihydro-2-[(1,1-dimethylethyl)dimethylsilyl]oxy]-1H-inden-1-ylester, 1:1 mixture of 1R,2R- and 1S,2S-diastereomers on indane ring(Compound 147d)

(a) Compound 147a ##STR285##

To a solution of 200 mg of OsO₄ in 100 mL of dry CH₂ Cl₂ were added 14.6g (125 mmol) of N-methylmorpholine oxide and 15.2 g (125 mmol) ofphenylboronic acid. To the resulting solution was added a solution of11.6 g of indene in 200 mL of CH₂ Cl₂ over 10 min. The resulting orangesolution was stirred at RT for 45 min and the reaction quenched with 10%sodium thiosulfate (RT, 1 hr). The mixture was diluted with EtOAc,washed with brine and the organic layer dried over Na₂ SO₄, filtered,and concentrated to give 27 g of a phenylboronate intermediate. Thesolid was dissolved in 250 mL of THF and 300 mL of 2N NaOH was added.The mixture was cooled to 0° C. and treated dropwise with 200 mL of 30%H₂ O₂. The mixture was stirred at RT for 2 h and at 50° C. for 1h. Aftercooling to RT, the aqueous layer was saturated with NaCl, diluted with500 mL of EtOAc and the organic layer separated and concentrated invacuo. The aqueous layer was extracted with EtOAc and the combinedorganics washed with brine. The organic layer was dried over Na₂ SO₄,filtered, and concentrated in vacuo to give 13.3 g of a residue. Flashchromatography of the residue on silica gel, eluting with 10-100%EtOAc-hexane, provided 6.64 g (44%) of Compound 147a.

(b) Compound 147b(i) ##STR286## and

Compound 147b(ii) ##STR287##

To a solution of the diol Compound 147a in 70 mL of DMF were added 6.4 g(42 mmol) of t-butyldimethylsilyl chloride and 3.6 g (53 mmol) ofimidazole. The mixture, containing Compounds 147b(i) and 147b(ii), wasstirred at RT for 24 h and the solvent removed in vacuo. The residue wastaken up in Et₂ O and washed with saturated NaHCO₃. The organic layerwas dried over Na₂ SO₄, filtered, and concentrated in vacuo to give 9.27g of a colorless oil. Flash chromatography on silica gel, eluting with0-10% Et₂ O-hexane, provided 1.38 g (26%) of Compound 147b(i) as acolorless oil.

(c) Compound 147c ##STR288##

Compound 147b(i) was converted to Compound 147c by a procedure analogousto that used for the synthesis of Compound 67a [pyridine was used asbase and co-solvent (3:1 CH₂ Cl₂ /pyridine)].

(d) Compound 147d ##STR289##

To a solution of 211 mg (0.476 mmol) of Compound 54 in 2 mL DMF at RTwere added 0.26 mL of i-Pr₂ NEt and then a solution of 225 mg (0.523mmol) of Compound 147c in 2 mL of CH₂ Cl₂. The mixture was stirred at RTfor 72 h then diluted with EtOAc and washed with 0.1N NaOH and brine.The organic layer was dried over Na₂ SO₄, filtered and concentrated invacuo to give 381 mg of crude material. Flash chromatography on silicagel, eluting with 95:5:0.25 CHCl₃ /CH₃ OH/NH₄ OH, provided 144 mg (41%)of the title Compound 147d.

EXAMPLE 148 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-dimethylethyl2,3-dihydro-2-hydroxy-1H-inden-1-yl ester(Compound 148) ##STR290##

To a solution of 143 mg (0.195 mmol) of Compound 147d in 1.0 mL of dryTHF at 0° C. was added 5 mL of a cold (0° C.) HF-pyridine solution(prepared by adding 1 mL of HF-pyridine to an ice cold solution of 2 mLpyridine in 7 mL of dry THF). The resulting solution was stirred at 0°C. for 2 h and at RT for 2 h. The mixture was diluted with CHCl₃ andwashed with saturated NaHCO₃ and brine. The organic layer was dried overNa₂ SO₄, filtered, and concentrated in vacuo to give 123 mg (˜100%) ofthe title Compound 148. The compound was triturated with Et₂ O andlyophilized from dioxane.

mp 135°-140° C. (soft at 75° C.); [α]²⁰ _(D=-) 3° (c 0.20, CH₃ OH)

Mass Spec. 620 (M+H)⁺

Elemental Analysis (%)

C₃₅ H₄₅ N₃ O₇ ·0.054 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              66.78  66.86                                                   H              7.38   7.28                                                    N              6.67   6.59                                                    ______________________________________                                    

EXAMPLE 149 Preparation of[1S-(1R*,2S*)]-[[[[2-(Trimethylsilyl)ethoxy]carbonyl]imino]bis-[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl1,1-dimethyl-4-[[(phenylmethoxy)carbonyl]amino]butyl ester (Compound 149e )

(a) Compound 149a ##STR291##

Compound 149a was prepared from 4-aminobutyric acid using a procedureanalogous to that used for the synthesis of Compound 85a.

(b) Compound 149b ##STR292##

Thionyl chloride (2.91 ml; 40 mmol) was added dropwise to a solution ofCompound 149a (4.74 g; 20 mmol) in 65 ml of MeOH at -20° C. Afterwarming to RT, the reaction mixture was stirred for 18 hr then dilutedwith Et₂ O and the resulting organic layer washed with saturated NaHCO₃and brine. After drying over MgSO₄, the organic layer was concentratedto afford 4.475 g (89%) of crude Compound 149b as a colorless oil. A 3.5g portion of this material was chromatographed on a 5×15 cm silica gelcolumn using hexane:EtOAc, 85:15 and hexane:EtOAc, 75:25 as the mobilephase to afford 3.28 g (84% yield) of Compound 149b as a colorlessliquid.

(c) Compound 149c ##STR293##

A solution of Compound 149b (500 mg; 2 mmol) in 4 ml of THF was added toa solution of MeLi (5.7 ml 1.4M in Et₂ O; 8 mmol) in 6 ml of THF at -78°C. After stirring 5 h at -78° C., the reaction mixture was quenched withsaturated NH₄ Cl and the resulting mixture extracted with Et₂ O. Theorganic layer was washed with H₂ O and brine. After drying over MgSO₄,the organic layer was concentrated and the resulting liquid purified ona 2.5×25 cm silica gel column using hexane:EtOAc, 6:4 as the mobilephase to afford 294 mg (59%) of Compound 149c as a colorless liquid.

(d) Compound 149d ##STR294##

4-Nitrophenylchloroformate (350 mg; 1.70 mmol) in 1 ml of CH₂ Cl₂ wasadded dropwise to a solution of Compound 149c (280 mg; 1.11 mmol) in 2.5ml of CH₂ Cl₂ and 0.5 ml pyridine. After stirring for 2 h at 0° C., anadditional 0.25 ml of pyridine and 4-nitrophenylchloroformate (225 mg;1.10 mmol) were added. The reaction mixture was stirred an additional 2h at 0° C. after which time 75 ml of Et₂ O was added. The organic layerwas washed with H₂ O, 0.1N NaOH, H₂ O, 5% cupric sulfate solution, H₂ O,and brine. Drying (MgSO₄) and concentration afforded a solid residuewhich was purified on a 2.5×20 cm silica gel column using hexane:EtOAc,75:25 to afford 370 mg (80%) of Compound 149d as a light yellow oil.

(e) Compound 149e ##STR295##

A mixture of Compound 48 (447 mg; 0.76 mmol) , Compound 149 d (357 mg;0.84 mmol) and i-Pr₂ NEt (0.29 ml; 1.70 mmol) in 1.5 ml of CH₃ CN wasstirred 72 h at RT. An additional quantity of i-Pr₂ NEt (0.15 ml; 0.86mmol) was added and the reaction mixture was heated to 45° C. for 18 h.The volatiles were removed in vacuo and the residue was partitionedbetween EtOAc and H₂ O. The organic layer was washed with H₂ O, 0.1NNaOH, H₂ O, saturated aq. KHSO₄, H₂ O, and brine. Dying (MgSO₄) andconcentration afforded a residue which was purified on a 2.5×15 cmsilica gel column using 4% MeOH/CH₂ Cl₂ to afford 540 mg (82%) ofCompound 149e as a white foamy solid.

¹ H NMR (DMSO-d⁶ ; 70° C.): δ0.01 (s, 9H)0.93 (t, J=8, 8.5 Hz, 2H), 1.19(s, 6H), 1.23 (s, 9H), 1.32 (m, 2H), 1.53 (m, 2H), 2.56 (m, 2H), 3.15(m, 2H), 3.57 (m, 4H), 3.68 (m, 2H), 4.07 (m, 2H), 4.79 (m, 2H), 5.00(s, 2H), 6.27 (brs, 2H), 6.90 (brs, 1H), 7.11 (m, 2H), 7.18 (m, 8H),7.31 (m, 5H).

EXAMPLE 150 Preparation of [1S-(1R*,2S*)],[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-promanediyl)]biscarbamic acid,1,1-dimethylethyl1,1-dimethyl-4-[[(phenylmethoxy)carbonyl]amino]butylester (Compound 150) ##STR296##

Compound 149e was converted to the title Compound 150 (white solid) by aprocedure analogous to that of Example 21.

mp 153°-155° C.; [α]₃₆₅ =-18.0° (c 0.10, MeOH).

Mass Spec. FAB+ion: (M+H)=721.

Analysis calc. for C₄₀ H₅₆ N₄ O₈ : C, 66.64; H, 7.83; N, 7.77;

Found: C, 66.36; H, 7.81; N, 7.75.

EXAMPLE 151 Preparation of[1S-(1R*,2S*)]-[[[[2-(Trimethylsilyl)ethoxy]carbonyl]imino]-bis[[2-hydroxy-1-(phenylmethyl)-3,1-proponediyl]]biscarbamicacid, 1,1-dimethylethyl 4-amino-1,1-dimethylbutyl ester (Compound 151)##STR297##

Compound 149e was converted to the title Compound 151 (colorless oil)using conditions analogous to those used for the synthesis of Compound7.

¹ H NMR (DMSO-d⁶ ; 70° C.): δ0.01 (s, 9H), 0.93 (t, J=9, 8 Hz, 2H), 1.20(s, 6H), 1.22 (m; buried under large singlets, 2H), 1.23 (s, 9H), 2.43(m, 2H), 2.55 (m, 2H), 2.93 (dd, J=3.5, 14 Hz, 2H), 3.05 (m, 4H), 3.53(m, 4H), 3.65 (m, 2H), 4.02 (m, 2H), 6.23 (brs, 2H), 7.12 (m, 10H).

EXAMPLE 152 Preparation of[1S-(1R*,2S*)]-[[[[2-(Trimethylsilyl)ethoxy]carbonyl]imino]-bis[[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl 1,1-dimethyl-4-[(phenylmethyl)amino]butyl ester(Compound 152) ##STR298##

NaHB(OAc)₃ (57 mg; 0.26 mmol) was added to a solution of Compound 151(125 mg; 0.178 mmol) and benzaldehyde (18 μl; 0.178 mmol) in1,2-dichloroethane at RT. After stirring for 3 h the solvent was removedin vacuo and the residue was partitioned between EtOAc and saturatedNaHCO₃. The organic layer was washed with H₂ O and brine, dried overMgSO₄ and concentrated to afford a crude residue which was purified on a2.5×8 cm silica gel column, using CH₂ Cl₂ :MeOH:NH₄ OH, 94.5:5.0:0.5 togive 125 mg (86%) of the title Compound 152 as a white foam.

¹ H NMR (DMSO-d⁶ ; 70° C.): δ0.01 (s, 9H), 0.93 (t, J=9, 8 Hz, 2H), 1.21(S, 6H), 1.23 (s, 9H), 1.33 (m, 2H), 1.58 (m, 2H), 2.48 (m, 2H), 2.57(m, 2H), 2.94 (dd, J=3, 14 Hz, 2H), 3.15 (m, 2H), 3.54 (m, 4H), 3.68 (m,2H), 3.72 (s, 2H), 4.05 (m, 2H), 4.80 (m, 2H), 6.26 (brs, 2H), 7.17 (m,10H), 7.30 (m, 5H).

EXAMPLE 153 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamicacid, 1,1-dimethylethyl 1,1-dimethyl-4-[(phenylmethyl)-amino]butyl ester(Compound 153) ##STR299##

Compound 152 was converted to the title Compound 153 (white solid) by aprocedure analogous to that used for the synthesis of Compound 21.

mp 128°-132° C.; [α]_(D) =-4.8° (c 0.42, MeOH).

Mass Spec. FAB+ion: (M+H)=677.

Analysis calc. for C₃₉ H₅₆ N₄ O₆ ·0.52 H₂ O: C, 68.27; H, 8.38; N, 8.16;

Found: C, 68.14; H, 8.25; N, 8.29.

EXAMPLE 154 Preparation of[R-(R*,S*)]-Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-dimethylethyl 1,1-dimethyl-2-phenylethyl ester (Compound 154)##STR300##

α,α-Dimethylphenethyl alcohol was converted to the title Compound 154(white solid) by a three-step procedure analogous to that used for theconversion of Compound 149c to Compound 150 (Et₃ N and DMF used in thecoupling of the p-nitrophenyl carbonate to Compound 48).

m.p. 161°-164° C.

EXAMPLE 155[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamicacid, 1,1-dimethylethyl 1,1-dimethyl-5-phenyl-2-pentynyl ester (Compound155b)

(a) Compound 159a ##STR301##

To a -78° C. solution of 4-phenyl-1-butyne (1.00 g, 7.68 mmol) in THF(4.40 mL) was added dropwise a solution of n-BuLi/hexane (3.24 mL of a2.49 M solution) and the resulting solution stirred at -78° C. for 1 h.A solution of acetone (0.59 mL, 8.07 mmol) in THF (1.0 mL) was addeddropwise at -78° C. and the resulting solution stirred at -78° C. for 3h at which point a solution of aqueous NH₄ Cl (9 mL of a 1 M solution)was added. The aqueous layer was extracted with EtOAc and the combinedorganic extracts dried (anhydrous Na₂ SO₄) and concentrated in vacuo togive a yellow oil. This crude material was chromatographed on silica gel(100 mL) eluting with 10:1 hexane:EtOAc to give Compound 155a (1.36 g,94%) as a clear colorless oil.

(b) Compound 155b ##STR302##

Compound 155a was converted to the title Compound 155b (white solid) bya three-step procedure analogous to that used for the conversion ofCompound 149c to Compound 150 (DMF used in the coupling of thep-nitrophenyl carbonate to Compound 48).

m.p. 140°-142° C.; α_(D) =+2.0° (c=0.2, MeOH)

Elemental Analysis (%)

for C₃₉ H₅₁ N₃ O₆ ·0.87 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              69.55  69.40                                                   H              7.89   7.73                                                    N              6.24   6.39                                                    ______________________________________                                    

EXAMPLE 156 Preparation of[1S-(1R*,2S*)]-2hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbamicacid, 1,1-dimethylethyl-1-methyl-1-phenylethyl ester Compound 156)##STR303##

Dimethylphenyl carbinol was converted to the title Compound 156 (whitesolid) by a three-step procedure analogous to that used for theconversion of Compound 149c to Compound 150 (Et₃ N and DMF used in thecoupling of the p-nitrophenyl carbonate to Compound 48).

m.p. 89°-92° C.

EXAMPLE 157 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-dimethylethyl 1,1-dimethyl-2(phenylmethoxy)-ethyl ester(Compound 157b)

(a) Compound 157a) ##STR304##

Compound 157a was prepared from benzyloxyacetyl chloride by a procedureanalogous to that used for the synthesis of Compound 149c.

(b) Compound 157b ##STR305##

Compound 157a was converted to the title Compound 157b (white solid) bya three-step procedure analogous to that used for the conversion ofCompound 149c to Compound 150 (DMF used in the coupling of thep-nitrophenyl carbonate to Compound 48).

m.p. 129°-135° C.; [α]²⁰ _(D) =-3.5° (c 0.5, CH₃ OH)

Elemental Analysis (%)

Calculated for C₃₇ H₅₁ N₃ O₇ ·1.37 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              65.89  65.52                                                   H              8.03   7.64                                                    N              6.23   6.60                                                    ______________________________________                                    

EXAMPLE 158 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamicacid, 1,1-dimethylethyl 1,1-dimethyl-3-(phenylmethoxy)-propyl ester(Compound 158b)

(a) Compound 158a ##STR306##

To a solution of 3M MeMgCl in THF (5 mL, 15 mmol) at -20° C. was added 5mL of THF and a solution of 4-benzyloxy-2-butanone (1.735 mL, 10 mmol)in 5 mL of THF. After the addition was complete, the reaction mixturewas warmed to RT and quenched with 10 mL of water. The mixture wasextracted with CH₂ Cl₂ and the organic phase was separated, dried(MgSO₄) and concentrated to provide the Compound 158a (1.8 g, 92%) as acolorless oil.

(b) Compound 158b ##STR307##

Compound 158a was converted to the title Compound 158b (white solid) bya three-step procedure analogous to that used for the conversion ofCompound 149c to Compound 150 (Et₃ N and DMF used in the coupling of thep-nitrophenyl carbonate to Compound 48).

m.p. 122°-125° C.; [α]²⁰ _(D) =-4.8° (c=0.5, CH₃ OH)

Elemental Analysis (%)

Calculated for C₃₈ H₅₃ N₃ O₇ ·1.30 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              66.41  66.58                                                   H              8.15   7.89                                                    N              6.11   5.94                                                    ______________________________________                                    

EXAMPLE 159 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis-[carbamicacid], 1,1-dimethylethyl 1-methyl-cyclopentyl ester (Compound 159)##STR308##

1-Methyl-1-cyclopentanol was converted to the title Compound 159 by athree-step procedure analogous to that used for the conversion ofCompound 149c to Compound 150 (DMF used in the coupling of thep-nitrophenyl carbonate to Compound 48).

m.p. 160°-162° C.; [α]_(D) =-4.3° (c 0.21)

Elemental Analysis (%)

for C₃₂ H₄₇ N₃ O₆ ·1.54 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              64.34  64.15                                                   H              8.45   8.03                                                    N              7.03   7.22                                                    ______________________________________                                    

EXAMPLE 160 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[carbamicacid], 1,1-dimethylethyl-1-methylcyclopentyl ester (Compound 160)##STR309##

1-Methyl-1-cyclobutanol was converted to the title Compound 160 (whitesolid) by a three-step procedure analogous to that used for theconversion of Compound 149c to Compound 150 (Et₃ N and DMF used in thecoupling of the p-nitrophenyl carbonate to Compound 48).

m.p. 179°-182° C.

Elemental Analysis (%)

C₃₁ H₄₅ N₃ O₆ ·0.47 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              66.00  65.89                                                   H              8.21   8.00                                                    N              7.45   7.56                                                    ______________________________________                                    

EXAMPLE 161 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1,1-dimethylethyl ester(Compound 161g)

(a) Compound 161a ##STR310##

A mixture of Compound 44a (1.0 g, 3.36 mmol) and 5% Pd on CaCO₃,poisoned with Pb (0.1 g, Aldrich) in 40 mL of MeOH was stirred under 1atm H₂ for 2 h. The catalyst was filtered off through a pad of Celiteand the filtrate concentrated. The crude product was purified bychromatography on a column of silica gel (2.5×35 cm) eluting with agradient of CH₂ Cl₂ -MeOH-aqueous NH₄ OH (98.0-1.8-0.2 to 95.0-4.5-0.5)to afford 170 mg (31% yield) of Compound 161a as a clear oil.

(b) Compound 161b ##STR311##

To 26.25 mL of 0.1M HClO₄ was slowly added 9.45 g (0.131 mol) ofisobutylene oxide and the reaction mixture stirred at RT for 30 mins.Water from the reaction mixture was distilled off first, followed by theproduct which distilled at 80° C. (10 mm Hg). Collection of puredistillate afforded Compound 161b as a colorless oil (6.4 g, 54%).

(c) Compound 161c ##STR312##

To a cooled (0° C.) solution of Compound 161b (2.0 g, 22.22 mmol) in 10mL of CH₂ Cl₂ was added Et₃ N (6.2 mL, 44.44 mmol) followed byt-butyldimethylsilyl chloride (3.684 g, 24.44 mmol). The reactionmixture was warmed to RT and after 2 h of stirring,N,N-dimethylaminopyridine (0.056 g, 0.44 mmol) was added. After stirringthe reaction mixture overnight, it was diluted with EtOAc and washedwith saturated NaHCO₃ followed by brine. The organic phase was dried(MgSO₄) and concentrated. The crude product obtained was chromatographedon silica gel eluting with a stepwise gradient of hexane to 50%EtOAc-hexane to afford Compound 161c (4.2 g, 92%) as a colorless oil.

(d) Compound 161d ##STR313##

To a solution of Compound 161c (1.0 g, 4.9 mmol) in 10 mL of dry CH₂ Cl₂cooled to 0° C. was added 5.0 mL of pyridine followed by slow additionof a solution of p-nitrophenylchloroformate (1.185 g, 5.88 mmol) in 6 mLof CH₂ Cl₂. The resulting suspension was stirred at 5° C. overnight. Thereaction mixture was diluted with EtOAc and washed with saturated NaHCO₃and brine. The organic phase was dried (MgSO₄) and concentrated toobtain the crude product which was flash chromatographed on silica geleluting with a stepwise gradient of hexane to 10% EtOAc-hexane to affordCompound 161d (1.05 g, 58%) as a viscous oil.

(e) Compound 161e ##STR314##

A solution of Compound 161a (70 mg, 0.429 mmol), Compound 161d (174 mg,0.472 mmol), and i-Pr₂ NEt (90 μL, 66.5 mg, 0.515 mmol) in 0.5 mL DMFwas stirred at RT for 72 h. The crude mixture was combined with thecrude mixture of a second, similar reaction run on exactly twice thescale. The combined crude mixture was concentrated and chromatographedon a column of silica gel (2.5×30 cm) eluting with 10% EtOAc-hexane toafford 423 mg (83% yield) of Compound 161e as a clear oil.

(f) Compound 161f ##STR315##

A stream of NH₃ was bubbled into a 5° C. solution of Compound 161e (420mg, 1.07 mmol) in 5 mL EtOH and 5 mL 30% aqueous NH₄ OH for 30 min. Theresulting solution was stirred at 5° C. for 15 min and then at RT for 18h. Argon was bubbled through the mixture for a few minutes and thesolvents were removed. The crude product was chromatographed on a columnof silica gel (2.5×15cm) eluting with a gradient of CH₂ Cl₂-MeOH-aqueous NH₄ OH (98.0-1.8-0.2 to 92.0-7.2-0.8) to afford 373 mg(85% yield) of Compound 161f as a white solid.

(g) Compound 161g ##STR316##

A solution of Compound 161f (223 mg, 0.543 mmol) and Compound 1b(i) (129mg, 0.489 mmol) was stirred in 1 mL of DMF at 115° C. for 3.5 h. Themixture was cooled to RT, concentrated to remove the bulk of the DMF,and the crude product was chromatographed on a column of silica gel(2.5×25cm) eluting with a gradient of CH₂ Cl₂ -MeOH-aqueous NH₄ OH(98.0-1.8-0.2 to 92.0-7.2-0.8) to afford 176 mg (53% yield) of Compound161g as a white solid.

EXAMPLE 162 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbamicacid, 1,1-dimethylethyl-2-hydroxy-1,1-dimethylethyl ester (Compound 162)##STR317##

To a solution of Compound 161g (170 mg, 0.252 mmol) in 1 mL THF wasadded 3 mL HOAc followed by 1 mL of H₂ O. The resulting mixture wasstirred at RT for 32 h. Solvents were removed and the crude product waschromatographed on a column of silica gel (2.5×25 cm) eluting with agradient of CH₂ Cl₂ -MeOH-aqueous NH₄ OH (98.0-1.8-0.2 to 92.0-7.2-0.8)to afford 107 mg (76% yield) of the title Compound 162 as a white solid.(Alternatively, Compound 157b was converted to Compound 162 by aprocedure analogous to that used for the synthesis of Compound 2.)

m.p. 153°-155° C.; [α]_(D) =-6.5° (c 0.54)

Elemental Analysis (%)

for C₃₀ H₄₅ N₃ O₇

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              64.38  64.07                                                   H              8.10   8.16                                                    N              7.51   7.91                                                    ______________________________________                                    

EXAMPLE 163 Preparation of[R-(R*,S*)]-[[[(Trimethylsilyl)-ethoxy]carbonyl]iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid,1,1-dimethylethyl2-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-1,1-dimethylethylester (Compound 163) ##STR318##

Compounds 161d and 48 were reacted by a procedure analogous to that usedfor the synthesis of Compound 143 (i-Pr₂ NEt used as base) to give thetitle Compound 163 (white solid).

¹ H NMR (CD₃ OD) δ7.23-7.08 (m, 10H) 4.13 (m, 2H) 3.81-3.60 (m, 6H)3.5-3.36 (m, 2H) 3.30 (m, 2H) 3.03 (m, 2H) 2.59 (m, 2H) 1.30-1.08 (15H)0.98 (m, 2H).

Mass Spec (FAB)-(M+H)+=704

EXAMPLE 164 Preparation of[R-(R*,S*)]-[[[(Trimethylsilyl)-ethoxy]carbonyl]iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl2-hydroxy-1,1-dimethylethyl ester (Compound 164)##STR319##

Compound 163 was converted to the title Compound 164 (white foam) by aprocedure analogous to that used for Compound 162. TLC (SiO₂) R_(f)=0.22 (50% EtOAc/Hexanes-PMA). Compound 164 was converted to Compound162 in 20% yield by a procedure analogous to that used for Compound 21.

EXAMPLE 165 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbamicacid, bis(2-hydroxy-1,1-dimethylethyl) ester (Compound 165c)

(a) Compound 165a ##STR320##

Compounds 32 and 161d (2 eq.) were reacted by a procedure analogous tothat used for the synthesis of Compound 161e to give Compound 165a.

(b) Compound 165b ##STR321##

Compound 165a was converted into Compound 165b (white solid) by aprocedure analogous to that used for the synthesis of Compound 2.

(c) Compound 165c ##STR322##

Compound 165b was converted to Compound 165c by a procedure analogous tothat used for the synthesis of Compound 162.

mp 140°-142 ° C.; [α]_(D) =-2.3° (c=0.2, CH₃ OH).

Mass Spec. (FAB) (M+H)⁺ =576;

Analysis calc. for C₃₀ H₄₅ N₃ O₈ ·1.42 H₂ O:

Calculated C, 59.93; H, 8.02; N, 6.99;

Found: C, 60.14; H, 7.68; N, 6.78.

EXAMPLE 166 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[carbamicacid], 1,1-dimethylethyl-4-methyltetrahydropyran-4-yl-ester (Compound166b)

(a) Compound 166a ##STR323##

Tetrahydro-4H-pyran-4-one was converted to Compound 166a by a procedureanalogous to that used for the synthesis of Compound 149c.

(b) Compound 166b ##STR324##

Compound 166a was converted to the title Compound 166b (white solid) bya three-step procedure analogous to that used for the conversion ofCompound 149c to Compound 150 (DMF used in the coupling of thep-nitrophenyl carbonate to Compound 48).

m.p. 144°-146° C.

Elemental Analysis (%)

C₃₂ H₄₇ N₃ O₇ ·0.54 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              64.55  64.64                                                   H              8.14   8.02                                                    N              7.06   6.97                                                    ______________________________________                                    

EXAMPLE 167 Preparation of[1S-(1R*,2S))]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamicacid, 1,1-dimethylethyl 1,1-dimethyl-5-phenyl-3-pentynyl ester (Compound167b)

(a) Compound 167a ##STR325##

To a -78° C. solution of 3-phenyl-1-propyne (4.00 g; 34.4 mmol) in THF(16 mL) was added a solution of n-BuLi (14.10 mL of a 2.52M solution inhexanes) followed 30 min later by BF₃ ·Et₂ O (4.24 mL; 34.5 mmol). Theresulting solution was stirred at -78° C. for 1 h at which point asolution of isobutylene oxide (2.55 g; 35.4 mmol) in THF (5 mL) wasadded. After 2 hr, a saturated aqueous NaHCO₃ solution was added and themixture was allowed to warm to RT. The mixture was partitioned betweenH₂ O and Et₂ O and the combined organic extracts washed with H₂ O andbrine, dried (anhydrous Na₂ SO₄) and concentrated in vacuo to give anorange-yellow oil. This material was chromatographed on silica gel (200mL) using 10:1 hexane:EtOAc as eluent to give Compound 167a (4.32 g;67%) as a pale yellow oil.

(b) Compound 167b ##STR326##

Compound 167a was converted to the title Compound 167b (white solid) bya three-step procedure analogous to that used for the conversion ofCompound 149c to Compound 150 (DMF used in the coupling of thep-nitrophenyl carbonate to Compound 48).

m.p. 120°-124° C.; [α]_(D) =3.2° (c 0.25, MeOH)

Mass spec (CI) 658 (M+H)

EXAMPLE 168 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbamicacid, 1,1-dimethylethyl2-methoxy-1,1-dimethylethyl ester (Compound 168b)

(a) Compound 168a ##STR327##

Methylmethoxy acetate was converted to Compound 168a by a procedureanalogous to that used for the synthesis of Compound 149c.

(b) Compound 168b ##STR328##

Compound 168a was converted to the title Compound 168b (white solid) bya three-step procedure analogous to that used for the conversion ofCompound 149c to Compound 150 (DMF used in the coupling of thep-nitrophenyl carbonate to Compound 48).

m.p. 151°-155° C.; [α]_(D) =-5.8° (c 0.32, MeOH)

Mass spec (CI) 574 (M+H)

EXAMPLE 169 Preparation of[1S-(1R*,2S*)]-Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl-3-hydroxy-1,1-dimethylpropyl ester (Compound169) ##STR329##

Compound 169 was obtained as a white solid from Compound 158b by aprocedure analogous to that used for the synthesis of Compound 2.

m.p. 133° C.; [α]²⁰ _(D) =-5.0° (c 0.2, CH₃ OH)

Elemental Analysis (%)

Calculated for C₃₁ H₄₇ N₃ O₇ ·0.95 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              63.02  62.98                                                   H              8.34   8.18                                                    N              7.11   7.15                                                    ______________________________________                                    

EXAMPLE 170 Preparation of[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydromy-1-(phenylmethyl)-propyl]-N²-[[(1-methyl-1H-benzimidazol-2-yl)-methoxy]carbonyl]-L-valinamide(Compound 170b)

(a) Compound 170a ##STR330##

A mixture of 2-hydroxymethylbenzimidazole (500 mg, 3.38 mmol), anhydrousK₂ CO₃ (467 mg, 3.38 mmol) and MeI (210 μl, 3.38 mmol) in 5 ml of DMFwas heated at 50° C. for 6 hr. The reaction was diluted with H₂ O andextracted with EtOAc. The extracts were washed with brine, dried (Na₂SO₄) and concentrated. The crude product was purified on a 30 ml silicacolumn eluting with MeOH:EtOAc (1:9) to give 146 mg (27%) of Compound170a.

(b) Compound 170b ##STR331##

Compound 170a was converted into the title Compound 170b by a three-stepsequence analogous to that used for the synthesis of Compound 67c(pyridine was used in the formation of the p-nitrophenyl carbonate; not-BuOH was used in the coupling of the p-nitrophenyl carbonate withL-valine; and no CH₂ Cl₂ was used in the reaction of the resulting acidwith Compound 54).

m.p. 148°-152° C.; [α]_(D) =-18.6° (c=0.22, MeOH)

High Res. Mass Spec. (FAB): C₄₀ H₅₅ N₆ O₇ =731.4142⁺ ; Δ=1.4 ppm.

EXAMPLE 171 Preparation of S-[1R*,2S*(2S*,3R*)]-N²-[[(2-Benzoxazolyl)methoxy]carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]-L-valinamide,(Compound 171b)

(a) Compound 171a ##STR332##

To a mixture of 2.50 g (22.9 mmol) of o-aminophenol and 1.74 g (22.9mmol) of glycolic acid in 50 mL of toluene was added 150 mg ofp-toluenesulfonic acid. The mixture was heated at reflux for 18 h withazeotropic removal of water. The resulting solution was cooled to RT,diluted with EtOAc and washed with 1N NaOH. The organic layer was dried(Na₂ SO₄), filtered through a pad of silica gel, and concentrated invacuo to give 1.57 g (47%) of an orange solid which was recrystallizedfrom EtOAc-hexane to afford 647 mg of Compound 171a (yellow solid). (b)Compound 171b ##STR333##

Compound 171a was converted into the title Compound 171b by a three-stepsequence analogous to that used for the synthesis of Compound 67c(pyridine was used in the formation of the p-nitrophenyl carbonate; not-BuOH was used in the coupling of the p-nitrophenyl carbonate withL-valine; and no CH₂ Cl₂ was used in the reaction of the resulting acidwith Compound 54).

m.p. 186°-188° C.

Elemental Analysis

Calc. for C₃₉ H₅₁ N₅ O₈ ·0.82 H₂ O C, 63.93; H, 7.24; N, 9.56

Found C, 64.02 H, 7.13 N, 9.47

Mass spec (FAB) 718 (M+H)

EXAMPLE 172 Preparation of[4S-4α,5α(4R*,5S*)]-5-[[[[3-[(1,1-Dimethylethoxy)carbonyl]-4-[(4-hydroxyphenyl)-methyl]-2,2-dimethyl-5-oxazolidinyl]methyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino]methyl]-2,2-dimethyl-4-(phenylmethyl)-3-oxazolidinecarboxylicacid, 1,1-dimethylethyl ester (Compound 172) ##STR334##

The mixture of Compound 20 (211 mg, 0.30 mmol), 2,2-dimethoxypropane(250 mg, 2.4 mmol) and p-TsOH (1.5 mg) in dry benzene (1.6 ml) wasrefluxed for 3.0 hrs with azeotropic removal of H₂ O, then stirred at RTovernight. The mixture was diluted with EtOAc then washed with saturatedNaHCO₃ and brine and dried over anhydrous Na₂ SO₄. Concentration invacuo followed by flash chromatography (hexane/ETOAc 10:1 to 6:1) on asilica gel column (190×20 mm) afforded 230 mg (98%) of Compound 172 as awhite foam. ¹ H-NMR (400 MHz, CDCl₃): 6.65-7.40 (m, 11H), 4.04-4.38 (m,6H), 3.20-3.64 (m, 4H), 2.81-3.06 (m, 4H), 1.25-1.94 (m, 30H), 0.95 (m,2H), 0.00 (s, 9H).

EXAMPLE 173

Preparation of [4S-4 α,5α(4R*,5S*)]-5-[[[[3-[(1,1-Dimethylethoxy)carbonyl]-2,2-dimethyl-4-[[4-[2-(4-morpholinyl)ethoxy]phenyl]methyl]-5-oxazolidinyl]methyl][[2-(trimethylsilyl)ethoxy]carbonyl]-amino]methyl]-2,2-dimethyl-4-(phenylmethyl)-3-oxazolidinecarboxylicacid, 1,1-dimethylethyl ester (Compound 173) ##STR335##

The mixture of Compound 172 (200 mg, 0.255 mmol), 4-(2-chloroethyl)morpholine (191 mg, 1.28 mmol) and K₂ CO₃ (88 mg, 0.638mmol) in dry DMF (1.0 ml) was heated at 100° C. for 14 hrs. The mixturewas diluted with EtOAc then washed with water, saturated NaHCO₃ andbrine and dried over anhydrous Na₂ SO₄. Concentration in vacuo followedby flash chromatography (100% CHCl₃ to CHCl₃ --MeOH--NH₄ OH: 99:1:0.1)on a silica gel column (200×20 mm) afforded 163 mg (71%) of Compound 173as a colorless oil. ¹ H-NMR (400 MHz, CDCl₃): 7.10-7.40 (m, 7H), 6.84(m, 2H), 4.02-4.39 (m, 8H), 3.76 (t, J=4.70, 4H), 3.20-3.60 (m, 4H),2.73 -3.03 (m, 6H), 2.60 (m, 4H), 1.24-1.83 (m, 30H), 0.95 (m, 2H), 0.00(s, 9H).

EXAMPLE 174

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-(4-morpholinyl)ethoxy]phenyl]butyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 174) ##STR336##

To Compound 173 (160 mg, 0.178 mmol) was added pre-cooled (10° C.) 96%formic acid (8.0 ml). The mixture was stirred at 5° C. for 15 min thenwas frozen (dry ice-acetone) and lyophilized overnight. The residue wastaken into CHCl₃ and washed with saturated NaHCO₃ and dried overanhydrous Na₂ SO₄. Concentration in vacuo followed by flashchromatography (100% CHCl₃ to CHCl₃ --MeOH--NH₄ OH: 98:2:0.2) on asilica gel column afforded 112 mg (77%) of Compound 174 as a colorlessoil. ¹ H-NMR (400 MHz, CD₂ Cl₂): 7.10-7.30 (m, 7H), 6.78 (m, 2H),4.45-4.85 (m, 3H), 4.13 (t, J=8.76, 2H), 4.00 (t, J=5.77, 2H), 3.55-3.90(m, 4H), 3.63 (t, J=4.70, 4H), 3.10-3.55 (m, 4H), 2.60-2.95 (m, 4H),2.70 (t, J=5.77, 2H), 2.48 (m, 4H), 1.31 and 1.30 (both s, 18H), 0.96(m, 2H), 0.00 (s, 9H).

EXAMPLE 175

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(4-[2-(4-morpholinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 175e)

(a) Compound 175a ##STR337##

To a solution of N-Boc-o-benzyl-L-tyrosine (25 g, 67.3 mmol) in dry THF(90 ml) cooled at -20° C. to -25° C. was added isobutyl chloroformate(8.7 ml, 67.3 mmol) followed by 4-methylmorpholine (6.8 ml, 67.3 mmol)and the mixture was stirred for 20 min. The precipitate was filtered andwashed with dry THF. The filtrate was cooled to -5° C. and poured into adiazomethane in ether solution (prepared from1-methyl-3-nitro-1-nitrosoguanidine (29.7 g, 202 mmol) as described inExample 1a(i)) at 0° C. The resulting yellow solution was kept at 0° C.for 2.0 h, then at RT overnight. Nitrogen was then bubbled through thesolution for 30 min, the solution diluted with Et₂ O (500 ml) and thenwashed with H₂ O, sat'd NaHCO₃, and brine, and dried (MgSO₄).Concentration in vacuo afforded a yellow residue, which was trituratedwith hexane (500 ml) to give 24.5 g (92%) of the correspondingα-diazoketone as an off-white solid. A solution of 48% aqueous HBr (5.8ml, 51.4 mmol) was added dropwise to the α-diazoketone (20.3 g, 51.4mmol) in 500 ml of 1,4-dioxane-DME (2:1) cooled at -5° C. After 30 min,saturated NaHCO₃ was added until pH=7.0 and the solvent was removedunder reduced pressure. The mixture was diluted with H₂ O and extractedwith EtOAc. The combined organic extracts were washed with H₂ O andbrine and dried (Na₂ SO₄). Concentration in vacuo followed byrecrystallization from EtOAc-hexane gave 20.9 g (91%) Compound 175a asan off-white solid.

(b) compound 175b ##STR338##

To a solution of Compound 175a (23.3 g, 50.0 mmol) in 250 ml of MeOH-THF(1:1) cooled at -5° C. was added, portionwise, NaBH₄ (2.0 g, 50.0 mmol).After 1 h, 10% KHSO₄ (75 ml) was added at 0° C. and the mixture wasallowed to warm to RT. The mixture was extracted with hot EtOAc and thecombined organic extracts were washed with H₂ O and brine, and dried(Na₂ SO₄). Concentration in vacuo followed by recrystallization fromEtOAc (350 ml) afforded 14.5 g (62%) of the syn bromohydrin as a whitesolid. HPLC analysis showed the diastereomeric ratio as 95:5. To asolution of the syn bromohydrin, prepared as above (115.2 g. 0.256mole), in 1.5 L of THF and 1.5 L of 100% EtOH was added a solution ofKOH (17.2 g of 87.6% pellets, 0.269 mole) in 300 mL of 100% EtOH at RT.After 15 min, 1 L of sat. aq. NH₄ Cl was added and the mixture thendiluted with 6 L of H₂ O to give a precipitate. The solid was filtered,washed with H₂ O, and extracted into 1 L of EtOAc. The organic phase wasdried (Na₂ SO₄) and concentrated in vacuo to give a solid which wastriturated with 1 L of hexane, to afford 79.3 g (84%) of Compound 175bas a white solid.

(c) Compound 175c ##STR339##

The mixture of Compound 175b (5.0 g, 13.5 mmol) and Pd(OH)₂ (500 mg) in100 ml EtOH and 25 ml of EtOAc was stirred under hydrogen atmosphere for4.5 hrs. The catalyst was removed by filtration and the filter cake waswashed with EtOH, MeOH, and EtOAc. The combined washes were concentratedin vacuo to give a 3.8 g (99%) of Compound 175c as a white solid.

(d) Compound 175d ##STR340##

To the mixture of Compound 175c (150 mg, 0.54 mmol),4-(2-hydroxyethyl)morpholine (141 mg, 1.07 mmol) and PPh₃ (282 mg, 1.07mmol) in 1.5 ml of dry THF was added DEAD (169 μl, 1.07 mmol). Theresulting mixture was stirred at RT overnight. Concentration in vacuofollowed by flash chromatography (CHCl₃ --i--PrOH--NH₄ OH: 99:1:0.1 to2:0.2) afforded 190 mg (90%) of Compound 175d as a white foam.

(e) Compound 175e ##STR341##

A mixture of Compound 175d (126 mg, 0.32 mmol) and Compound 16b (90 mg,0.32 mmol) in 0.64 ml of dry DMF was heated at 100° C. for 4.0 hrs.Concentration in vacuo followed by flash chromatography (CHCl₃--MeOH--NH₄ OH: 99:1:0.1 to 96:4:0.4) afforded, after trituration withchloroform/hexane, 90 mg (44%) of Compound 175e. m.p.: 140.0°-141.0° C.;[α]_(D) =-3.25° (c 0.246, MeOH). MS (FAB): 673⁺ (M+H)⁺. Anal. Calc. forC₃₆ H₅₆ N₄ O₈ ·0.42H₂ O: C, 63.55; H, 8.42; N, 8.24. Found: C, 63.73; H,8.43; N, 8.06.

Alternatively, Compound 175e was prepared as follows. Compound 174 wasconverted to the title Compound 175e by a procedure analogous to thatused for the synthesis of Compound 21. Flash chromatography (100% CHCl₃to CHCl₃ --MeOH--NH₄ OH: 0:4.5:0.5) on a silica gel column gave Compound175e as a white solid which was lyophilized from 1,4-dioxane to give awhite lyophilate.

EXAMPLE 176

Preparation of [4S-4α,5α(4R*,5S*)]-5-[[[[3-[(1,1-Dimethylethoxy)carbonyl]-2,2-dimethyl-4-phenylmethyl-5-oxazolidinyl]methyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino]methyl]-2,2-dimethyl-4-[[4-[2-(2-pyridinyl)ethoxy]phenyl]methyl]]-3-oxazolidinecarboxylicacid, 1,1-dimethylethyl ester (Compound 176) ##STR342##

To the mixture of Compound 172 (184 mg, 0.235 mmol),2-(2-hydroxyethyl)pyridine (40 μl, 0.352 mmol) and PPh₃ (93 mg, 0.352mmol) in dry THF (0.5 ml) was added DEAD (55 μl, 0.352 retool). Theresulting yellow solution was stirred at RT overnight. Concentration invacuo followed by flash chromatography (hexane/EtOAc 4:1) on a silicagel column afforded 143 mg (69%) of Compound 176 as a colorless oil. ¹H-NMR (400 MHz, CD₃ OD): 8.49 (d, J=5.13, 1H), 7.79 (m, 1H), 7.44 (d,J=7.69, 1H), 7.13-7.38 (m, 8H), 6.87 (d, J=7.69, 1H), 4.34 (t, J=6.41,2H), 4.03-4.35 (m, 6H), 3.30-3.55 (m, 4H), 3.26 (t, J=6.41, 2H),2.75-3.00 (m, 4H) , 1.30-1.79 (m, H), 0.93 (m, 2H), 0.00 (s, 9H).

EXAMPLE 177

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl][[2-(trimethylsilyl)ethoxy]carbonyl]-amino]-2-hydroxy-1-[[4-2-(2-pyridinyl)ethoxy]-phenyl]methyl]propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 177) ##STR343##

a) Removal of bis-acetonide

To Compound 176 (143 mg, 0.161 mmol) was added pre-cooled (10° C.) 96%formic acid (4.0 ml). The mixture was stirred at 5° C. for 15 min thenwas frozen (dry ice-acetone) and lyophilized overnight to give an oilyresidue.

b) The above residue was dissolved in MeOH (2.3 ml). To this solutionwas added Et₃ N (40 μl, 0.242 mmol) and di-t-butyldicarbonate (20 μl,0.08 mmol). The mixture was stirred at RT overnight. Concentration invacuo followed by flash chromatography (100% CHCl₃ to CHCl₃ --MeOH--NH₄OH: 97:3:0.3) on a silica gel column afforded 106 mg (81%) of Compound177 as a white foam. ¹ H-NMR (400 MHz, CD₃ OD): 8.42 (m, 1H), 7.72 (m,1H), 7.36 (m, 1H), 7.03-7.25 (m, 8H), 6.75 (d, J=7.69, 2H), 4.24 (t,J=6.41, 2H), 4.12 (t, J=8.55, 2H), 3.50-3.80 (m, 6H), 3.17 (t, J=6.41,2H), 2.88-3.30 (m, 4H), 2.35-2.64 (m, 2H), 1.25 (s, 18H), 0.99 (t,J=8.55, 2H), 0.00 (s, 9H).

EXAMPLE 178

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(4-[2-(2-pyridinyl)ethoxy]phonyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethyl-ethyl ester (Compound 178) ##STR344##

A mixture of Compound 177 (0.106 g; 0.131 mmol) and solid n-Bu₄ NF·nH₂ O(0.103 g; 0.393 mmol) in 0.56 ml THF was stirred at 50° C. for 4 h.After cooling to RT, 1 g of celite was added and the solvent removed invacuo. Flash chromatography (CHCl₃ --MeOH--NH₄ OH: 98:2:0.2 to 95:5:0.5)on a silica gel column followed by trituration with Et₂ O-hexane gave0.04 g of Compound 178 as a light yellow solid. m.p.: 125.0°-126.5° C.;[α]_(D) =-4.84° (c 0.248, MeOH). MS (FAB): 665⁺ (M+H)⁺. Anal. Calc. forC₃₇ H₅₂ N₄ O₇ ·0.53H₂ O:

C, 65.89; H, 7.93; N, 8.13. Found: C, 66.07; H, 7.85; N, 8.13.

EXAMPLE 179

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[[4-(phenylmethoxy)-phenyl]methyl]propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 179c)

(a) Compound 179a ##STR345##

Compound 18 was converted to Compound 179a in 27% yield by a procedureanalogous to that used for the synthesis of Compound 19 except that thereaction was only allowed to proceed to partial completion.

(b) Compound 179b ##STR346##

Compound 179a was converted to Compound 179b by a procedure analogous tothat used for the synthesis Compound 131 except that MeOH was used inplace of DMF and the reaction was run at RT overnight.

(c) Compound 179c ##STR347##

Compound 179c was obtained as a white solid from Compound 179b by aprocedure analogous to that used for the synthesis of Compound 21. m.p.159°-161° C.; [α]_(D) =-8.97° (c 0.245, DMSO) M.S. (FAB): 650⁺ (M+H)⁺.

EXAMPLE 180

Preparation of[1S-(1R,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamicacid, 4-amino-1,1-dimethylbutyl 1,1-dimethylethyl ester, fumarate (2:3)salt (Compound 180) ##STR348##

Compound 180 was obtained as a white powder from Compound 150 by aprocedure analogous to that used for the synthesis of Compound 84. mp123°-130° C.; [α]₃₆₅ =-12.7 (c 0.15, MeOH). Mass Spec. FAB+ions:(M+H)=587. Analysis calc. for C₃₂ H₅₀ N₄ O₆ ·1.5 C₄ H₄ O₄ ·2.96 H₂ O:

C, 56.06; H, 7.66; N, 6.88; Found: C, 56.21; H, 7.42; N, 6.73.

EXAMPLE 181

Preparation of[1S,[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,2-Dimethylpropyl)sulfonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 181b)

(a) Compound 181a ##STR349##

To a stirred solution of Compound 48 (300 mg, 0.51 retool) in 2 ml ofdry CH₃ CN at -20° C. under argon was added2,2-dimethylpropyl-1-sulfonylchloride (Synthesis, 489 (1974)) (96 mg,0.56 mmol) followed by i--Pr₂ NEt (79 mg, 0.61 mmol). Afterapproximately 2 hr at -5° C., additional sulfonylchloride (48 mg, 0.28retool) and i--Pr₂ NEt (40 mg, 0.31 retool) was added at -20° C. Themixture was re-warmed to ca. -5° C. and stirred at that temperature for4 hr, at which time the solution was adsorbed onto celite andchromatographed on a column (2.5×30 cm) of silica gel eluting with agradient of hexane and EtOAc to afford 101 mg (27% yield) of Compound181a as a clear solid foam.

(b) Compound 181b ##STR350##

Compound 181b was obtained as a white lyophilate from Compound 181a by aprocedure analogous to that used for the synthesis of Compound 21. m.p.134°-137° C. ("shrinkage" at 65°-134° C.); [α]_(D) =-11.0° (c 0.77,MeOH) Elemental Analysis (%) Calc. for C₃₀ H₄₇ N₃ O₆ S·0.7 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              61.03  61.05                                                   H              8.26   8.17                                                    N              7.12   7.10                                                    ______________________________________                                    

Example 182

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[(1,1-Dimethylethyl)-sulfinyl]amino-2-hydroxy-4-phenylbutyl]amino]2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 182c)

(a) Compound 182a ##STR351##

To a solution of t-butyl disulfide (4.8 mL, 25 mmol) in 25 mL of HOAc at0° C. was added 3.18 mL (31.25 mmol) of 30% aqueous H₂ O₂. The reactionmixture was stirred at 5° C. for 24 h and then poured into 100 mL of icewater. The product was extracted with CH₂ Cl₂ and the combined extractswashed with sat. NaHSO₃, sat. NaHCO₃ and H₂ O. The organic phase wasdried (MgSO₄) and concentrated to obtain a colorless oil. Cl₂ gas (1.93g, 27.18 mmol) was condensed at -78° C. and cannulated into a cooledsolution (0-10° C.) of the above oil in 25 mL of dry CH₂ Cl₂. Theresulting yellow solution was allowed to warm to RT and concentrated toobtain a dark yellow oil which was distilled at 47°-48° C. (9 mm Hg) toobtain pure Compound 182a (0.72 g, 20%) as a colorless oil.

(b) Compound 182b ##STR352##

Compound 182a was converted to Compound 182b by a procedure analogous tothat used for the synthesis of Compound 181a except that Et₃ N/CH₂ Cl₂was used.

(c) Compound 182c ##STR353##

Compound 182c was prepared as a white solid from Compound 182b by aprocedure analogous to that used for Compound 21. m.p. 152°-155° C.("shrinkage" at 55°-70° C.)

EXAMPLE 183

Preparation of[1S-[1R*,25*(2S*,3R*)]]-[3-[[3-[[(2,2-Dimethylethyl)sulfonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester. (Compound 183b)

(a) Compound 183a ##STR354##

To a solution of Compound 182b (0.22 g, 0.318 mmol) in 2.5 mL of CH₂ Cl₂cooled to 0° C. was added 1.5 mL of saturated aq. NaHCO₃. The suspensionwas vigorously stirred and a solution of 75% (80 mg, 0.35 mmol) in 2.5mL of CH₂ Cl₂ was added dropwise. The reaction mixture was stirred for90 min after which time it was warmed to RT, diluted with CH₂ Cl₂ andwashed with sat. NaHSO₃ followed by sat. NaHCO₃. The organic phase wasdried (MgSO₄) and concentrated. The crude material was flashchromatographed of silica eluting with a step-wise gradient of 25%EtOAc-hexane to 80% EtOAc-hexane to obtain 0.193 g (85%) of Compound183a as a white solid.

(b) Compound 183 b ##STR355##

Compound 183b was prepared as a white solid by a procedure analogous tothat used for the synthesis of Compound 21. m.p. 86°-90° C. ("softening"at 75°-86° C.); [α]²⁰ _(D) =-18.7° (c=0.2, CH₃ OH).

EXAMPLE 184

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)thio)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 184b)

(a) Compound 184a ##STR356##

Compound 184a was prepared from t-butyl mercaptan by a procedureanalogous to that used for the synthesis of Compound 67a (pyridine wasused).

(b) Compound 184b ##STR357##

Compounds 184a and 54 were reacted by a procedure analogous to that usedfor the synthesis of Compound 147d to afford Compound 184b as a whitesolid. m.p. 140°-141° C. ("softening" at 134°-140° C.); [α]²⁰ _(D)=-20.0° (c=0.05, CH₃ OH).

EXAMPLE 185

Preparation of[2S-[2R*,3S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino-2-hydroxy-4-phenylbutyl]amino-2-hydroxy-4-phenylbutyl]carbamicacid, phenylmethyl ester (Compound 185d )

(a) Compound 185a ##STR358##

A 3:2 mixture of Compounds 26a(i) and 26a(ii) was converted intoCompound 185a by a procedure analogous to that used for the synthesis ofCompound 16b (except that the reaction was performed in NH₃ saturatedMeOH at 50°-60° C. in a sealed vessel).

(b) Compound 185b ##STR359##

Compound 185a was reacted with Cbz chloride by a procedure analogous tothat used for the synthesis of Compound 122 to give Compound 185b (CH₂Cl₂ used in place of DMF).

(c) Compound 185c ##STR360##

Compound 185b was converted to Compound 185c by a procedure analogous tothat used for the synthesis of Compound 32.

(d) Compound 185d ##STR361##

Compounds 185c and 1b(i) were reacted by a procedure analogous to thatused for the synthesis of Compound 4b to give the title Compound 185d asa white solid after silica gel chromatography (28 g) eluting the columnwith a stepwise gradient of CH₂ Cl₂ :MeOH:NH₄ OH (98.9:1.0:0.1) to CH₂Cl₂ :MeOH:NH₄ OH (94.5:5.0:0.5), using 1% increments for MeOH and 0.1%increments for NH₄ OH and trituration with Et₂ O to separate theisomers. MS: (M+H)⁺ @ 578⁺. mp 120°-121° C.; [α]_(D) =-5.0° (c 0.10,MeOH). Analysis calc. for C₃₃ H₄₃ N₃ O₆ ·0.01H₂ O:

C, 68.59; H, 7.50; N, 7.27; Found: C, 68.52; H, 7.65; N, 7.34.

EXAMPLE 186

Preparation of[3S-[3R*,2(R*,S*)[2S*,3R*)]-3-[[3-(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-4-phenylbutyl]carbamicacid, phenylmethyl ester (Compound 186) ##STR362##

Compound 186 was prepared as a colorless solid from a 1:1 mixture of1b(i) and 1b(ii) by a procedure analogous to that used for the synthesisof Compound 185d. mp 90°-95° C.; [α]_(D) =-4.0° (c 0.10, MeOH). MS:(M+H)⁺ @578⁺ Analysis calc. for C₃₃ H₄₃ N₃ O₆. 0.9 6H₂ O:

C, 68.40; H, 7.81; N, 7.25; Found: C, 68.39; H, 7.57; N, 7.26.

EXAMPLE 187

Preparation of[2S-[2R*,3S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-4-phenylbutyl]carbamicacid, 1,1-dimethylethyl ester (Compound 187) ##STR363##

Compound 187 was obtained as a white solid from the (S)-hydroxyldiastereomer of Compound 185d by removing the Cbz group using reactionconditions analogous to those used for the synthesis of Compound 7 andputting on the Boc group using a procedure analogous to that used forthe synthesis of Compound 20 (CH₂ Cl₂ /DMF used as solvent). m.p. 143°C.-144° C.; [α]_(D) =-4.0° (c=0.09, MeOH) Elemental Analysis (%) C₃₃ H₄₅N₃ O₆, calculated for 0.44 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              65.31  65.09                                                   H              8.38   8.22                                                    N              7.62   7.83                                                    ______________________________________                                    

EXAMPLE 188

Preparation of[3S-[3R*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenyl-butyl]amino]-2-hydroxy-4-phenylbutyl]carbamicacid, 1,1-dimethylethyl ester, 2:1 diastereomer mixture (Compound 188)##STR364##

Compound 188 was obtained as a white solid from Compound 186 by removingthe Cbz group using reaction conditions analogous to those used for thesynthesis of Compound 7 and putting on the Boc group using a procedureanalogous to that used for the synthesis of Compound 20 (CH₂ Cl₂ /DMFused as solvent ) . m.p. 93° C.-94° C.; [α]_(D) =+4.0° (c=0.10, MeOH)Elemental Analysis (%) C₃₀ H₄₅ N₃ O₆, calculated for 0.2 moles H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              65.84  65.74                                                   H              8.36   8.39                                                    N              7.68   7.78                                                    ______________________________________                                    

EXAMPLE 189

Preparation of[2R-[2R*,3R*(2R*,3S*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-4-phenylbutyl]-carbamicacid, phenylmethyl ester (Compound 189) ##STR365##

Compound 189 was obtained as a white solid from the (R)-hydroxyldiastereomer of Compound 185a by a procedure analogous to that ofExample 185d. m.p. 112° C.-113° C.; [α]_(D) =+3.0° (c=0.09, MeOH)Elemental Analysis (%) C₃₃ H₄₃ N₃ O₆, calculated for 0.27 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              68.03  67.94                                                   H              7.53   7.35                                                    N              7.21   7.30                                                    ______________________________________                                    

EXAMPLE 190

Preparation of[2R-[2R*,3R*(2R*,3S*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenyl-butyl]amino]-2-hydroxy-4-phenylbutyl]carbamicacid, 1,1-dimethylethyl ester (Compound 190) ##STR366##

Compound 190 was obtained as a white solid from Compound 189 by atwo-step procedure analogous to that used for the synthesis of Compound187. m.p. 132° C.-134° C.; [α]_(Hg) =+1.0° (c=0.08, MeOH) ElementalAnalysis (%) C₃₀ H₄₅ N₃ O₆ calculated for 1.34 moles H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              65.63  65.27                                                   H              7.96   7.83                                                    N              6.96   7.32                                                    ______________________________________                                    

EXAMPLE 191

Preparation of[1S-(1R*,2S*)]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-2-(phenylmethyl)propyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethyl-ethyl ester (Compound 191e)

(a) Compound 191a ##STR367##

Compound 191a was prepared from epoxypropyl benzene by a procedureanalogous to that used for the synthesis of Compound 16b except that NH₃saturated MeOH was used at 90° C. in a sealed vessel.

(b) Compound 191b ##STR368##

Compound 191b was prepared from Compound 191a by a procedure analogousto that used for the synthesis of Compound 131 (THF/H₂ O used).

(c) Compound 191c ##STR369##

DMSO (0.17 ml, 2.40 mmol) was added to a stirred solution of (COCl)₂(0.104 ml, 1.20 mmol) in dry CH₂ Cl₂ (5.0 ml) at -78° C. After 15 min, asolution of Compound 191b (0.10 g, 0.40 mmol) in CH₂ Cl₂ (5.0 ml) wasadded. The reaction mixture remained at -78° C. for 40 min before addingEt₃ N (0.39 ml, 2.80 mmol), and warming to 0° C. for 4 min. The yellowreaction mixture was then quenched with saturated NH₄ Cl and the aqueouslayer extracted with EtOAc. The organic layer was washed with saturatedNaHCO₃, dried (Na₂ SO₄) and concentrated in vacuo to afford 0.109 g ofCompound 191c as a yellow oil.

(d) Compound 191d ##STR370##

To a solution of Compound 191c (0.10 g, 0.40 mmol) in THF (30 ml) wasadded the ylide (0.60 ml, 0.962M) freshly prepared by refluxingtrimethylsulfoxonium chloride (3.75 g, 29.16 mmoles) and NaH (0.693 g,28.88 mmol, 60% oil dispersion washed with hexane) in dry THF (30 ml)for 3.5 h. After stirring at 0° C. for 75 seconds, saturated NaHCO₃ wasadded and the reaction mixture was partitioned between EtOAc and NaHCO₃solution. The volatiles were evaporated to afford a yellow oil which isa mixture of Compounds 191c and 191d (1:1). The oil was dried byazeotroping with toluene three times and placing under high vacuum, thenresubmitting to the reaction conditions. The isolated crude material waspurified on a silica gel column (10 g), eluting the column with CH₂ Cl₂:MeOH:NH₄ OH (98.9:1.0:0.1, 97.8:2.0:0.2 and 96.7:3.0:0.3) to afford0.69 g (66%) of Compound 191d as a yellow oil.

(e) Compound 191e ##STR371##

Compounds 191d and 16b were reacted by a procedure analogous to that ofExample 4b (except in MeOH at 50° C.) to give Compound 191e as acolorless foam. m.p. 65°-67° C.; [α]_(D) =-3-0° (c 0.10, MeOH)Calculated for C₃₀ H₄₅ N₃ O₆ ·0.35 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              65.52  65.36                                                   H              8.37   8.42                                                    N              7.64   7.80                                                    ______________________________________                                    

EXAMPLE 192

Preparation of[1S-[1R*,2S*(3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-2-methyl-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbamicacid, 1,1-dimethylethyl ester (Compound 192c)

(a) Compound 192a ##STR372##

KN(TMS)₂ (6.08ml, 3.04 mmol) was added dropwise to a mixture of MePPh₃+Br⁻ (1.19 g, 3.34 mmol) in toluene (8 ml) at -78° C. After 5 min, themixture was warmed to RT and stirred for 15 min. After recooling thereaction to -78° C., a solution of3S-3-[(1,1-dimethylethoxycarbonyl)amino]-4-phenyl-2-butanone [Godfrey etal., Tetrahedron Letters, 28, 1603 (1987)](0.40 g, 1.52 mmol) in toluene(2 ml) was added. The reaction was quenched after 35 min with pH 7buffer and the aqueous layer extracted with EtOAc. The combined extractswere dried (Na₂ SO₄) and concentrated in vacuo to afford 0.159 g ofCompound 192a as a white solid (42% yield).

(b) Compound 192b ##STR373##

m-CPBA (0.13 g, 0.61 mmole) was added to a stirred solution of Compound192a (0.16 g, 0.61 mmol) in CH₂ Cl₂ (2 ml) at 0° C. After 30 min, thereaction mixture was warmed to RT and stirred for an additional 30 minbefore quenching with pH 7 buffer and partitioning between aq. NaHCO₃and EtOAc. The organic extracts were dried (Na₂ SO₄) and concentrated invacuo to afford 0.17 g of a white solid. This crude material waspurified by silica gel chromatography (20 g), eluting the column with10% EtOAc/hexane to afford 0.129 g of Compound 192b as a white solid(87% yield).

(c) Compound 192c ##STR374##

Compounds 192b and 16b were reacted by a procedure analogous to that ofExample 4b (except that the reaction was run in MeOH at 50° C.) to givethe title Compound 192c as a colorless foam. m.p. 63°-66° C.; [α]_(D)=-3.0° (c 0.10, MeOH) Elemental Analysis (%) Calc. for C₃₁ H₄₇ N₃ O₆·0.42 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              65.98  66.15                                                   H              8.37   8.52                                                    N              7.45   7.28                                                    ______________________________________                                    

EXAMPLE 193

Preparation of[1S-[1R*,2S*(3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 193b)

(a) Compound 193a ##STR375##

To a solution of Compound 1a(iii) (197 mg, 0.68 mmol), Compound 4a (250mg, 0.66 mmol), and NaI (99 mg, 0.66 mmol) in DMF (1.8 mL) was addedNaHCO₃ (200 mg, 2.38 mmol). The suspension was stirred at RT for 18.5 hand then partitioned between EtOAc and H₂ O. The organic extracts weredried (Na₂ SO₄) and concentrated in vacuo to give an oily-solid residuewhich was purified by flash chromatography (silica gel, 3 by 11 cm),eluting with MeOH:NH₄ OH:CH₂ Cl₂ (0.5:0.05:99.45 and then 1:0.1:98.9) togive Compound 193a (130 mg, 31% yield) as a colorless solid. R_(f) =0.36(4:0.4:95.6; MeOH:NH₄ OH:CH₂ Cl₂); Mass Spec. (FAB): 632 (M+H).

(b) Compound 193b ##STR376##

Compound 193b was prepared as a colorless solid from Compound 193a by aprocedure analogous to that of Example 7 (1:1 THF:MeOH used). m.p. dec.116°-120° C. Mass Spec. (CI/NH₃): 542 (M+H). Anal. Calc. for C₃₀ H₄₃ N₃O₆ ·0.26 H₂ O:

C, 65.94; H, 8.03; N, 7.69 Found: C, 66.00; H, 8.05; N, 7.63

EXAMPLE 194

Preparation of[2S-(2R*,2R*)]-[[(Phenylmethyl)-imino]bis[2-hydroxy-4-phenyl-3,1-butanediyl]]bis-carbamicacid, bis(1,1-dimethylethyl)ester (Compound 194b)

(a) Compound 194a ##STR377##

Compound 194a was prepared from 1 eq. of benzyl amine and 2.2 eq. ofCompound 1a(iii) by a procedure analogous to that used in Example 193a.

(b) Compound 194b ##STR378##

Compound 194b was prepared as a white foam from Compound 194a by aprocedure analogous to that used for the synthesis of Compounds 1a(iv)and 1a(v) except that 95% EtOH was used. m.p. 60.0°-62.0° C. ElementalAnalysis (%) C₃₇ H₅₁ N₃ O₆

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              70.11  69.67                                                   H              8.11   8.05                                                    N              6.63   6.43                                                    ______________________________________                                    

EXAMPLE 195

Preparation of[1S-[1R*(3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-(phenylmethyl)amino]-2-oxo-1-(phenylmethyl)propyl]-carbamicacid, 1,1-dimethylethyl ester. (Compound 195) ##STR379##

Compound 195 was also isolated as a white solid from the reactionmixture of Example 194b. m.p. (161.0° C. softens) 176.0°-177.0° C.Elemental Analysis (%) C₃₇ H₄₉ N₃ O₆

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              70.34  69.85                                                   H              7.82   7.86                                                    N              6.65   6.77                                                    ______________________________________                                    

EXAMPLE 196

Preparation of(3S,3S')-[[(Phenylmethyl)nitrilo]-bis(2-hydroxy-5-methyl-3,1-hexandiyl)]-biscarbamicacid, bis(1,1-dimethylethyl)ester (Compound 196b)

(a) Compound 196a ##STR380##

Compound 196a was prepared from Boc-L-leucine by a procedure analogousto that used for the synthesis of Compound 1a(iii).

(b) Compound 196b ##STR381##

Compound 196b was prepared as a white foam by a two-step procedureanalogous to that of Example 194b. m.p. 54.0°-55.0° C. ElementalAnalysis (%) C₃₁ H₅₅ N₃ O₆ ·0.53 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              64.72  64.63                                                   H              9.82   9.27                                                    N              7.30   7.39                                                    ______________________________________                                    

EXAMPLE 197

Preparation of [1S-[1R*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-4-phenylbutyl]-methylamino]-2-oxo-1-phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 197b)

(a) Compound 197a ##STR382##

Compound 197a was prepared from Compound 1b(i) and MeNH₂ by a procedureanalogous to that used for the synthesis of Compound 4a except that thereaction was run in EtOH at RT.

(b) Compound 197b ##STR383##

Compound 197b was prepared as a white foam from Compounds 197a andla(iii) by a procedure analogous to that of Example 193a. m.p.120.0°-122.0° C. Elemental Analysis (%) C₃₁ H₄₅ N₃ O₆ 19 0.40 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              66.14  66.01                                                   H              8.20   8.08                                                    N              7.46   7.28                                                    ______________________________________                                    

EXAMPLE 198

Preparation of[1S-[1R*,2S*(3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-4-phenylbutyl]-methylamino]-2-hydroxy-1-(phenylmethyl)propyl-carbamicacid, 1,1-dimethylethyl ester (Compound 198) ##STR384##

Compound 198 was prepared as a white foam from Compound 197b by aprocedure analogous to that used for the synthesis of Compounds 1a(iv)and 1a(v) except that 95% EtOH was used. m.p. 62.0°-70.0° C. ElementalAnalysis (%) C₃₁ H₄₇ N₃ ·0.18 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              66.76  66.37                                                   H              8.49   8.70                                                    N              7.53   7.27                                                    ______________________________________                                    

EXAMPLE 199

Preparation of [1S-[1R*(2R*,3R*)]]-3-[[3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-4-phenylbutyl]-methylamino]-2-oxo-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 199) ##STR385##

Compound 199 was prepared as a white foam from Compound 1b(ii) by aprocedure analogous to that of Example 197b. m.p. 72.0°-80.0° C.Elemental Analysis (%) C₃₁ H₄₅ N₃ O₆

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              67.00  66.84                                                   H              8.16   8.14                                                    ______________________________________                                    

EXAMPLE 200

Preparation of[1S-[1R*,2R*(1R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-4-phenylbutyl]-methylamino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamicacid, 1,1-dimethylethyl ester (Compound 200). ##STR386##

Compound 200 was prepared as a white foam from Compound 199 by aprocedure analogous to that used for the synthesis of Compounds 1a(iv)and 1a(v) except that 95% EtOH was used. m.p. 70.0°-75.0° C. ElementalAnalysis (%) C₃₁ H₄₇ N₃ O₆ ·0.85 H₂ O

    ______________________________________                                                     Calc.                                                                              Found                                                       ______________________________________                                        C              64.98  65.31                                                   H              8.57   8.30                                                    N              7.33   7.00                                                    ______________________________________                                    

EXAMPLE 201

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[3-(4-morpholinyl)propoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 201d)

(a) Compound 201a ##STR387##

Ethyl-3-bromoproprionate (3.20 ml; 25 mmol) was added to a mixture ofmorpholine (2.20 ml; 25 mmol) and Na₂ CO₃ (2.78 g; 26 mmol) in 4.5 ml ofEtOH at RT. The mixture was stirred for 30 min at RT and 4 h at reflux.After cooling to RT and filtering, the filtrate was concentrated and theresidue was dissolved in H₂ O. The pH was adjusted to ˜1.5 withsaturated KHSO₄ and the acidic mixture was washed with Et₂ O. Solid K₂CO₃ was added to the aqueous layer until a pH of ˜9 was reached. Thebasic mixture was extracted with CH₂ Cl₂, dried (MgSO₄) and concentratedto afford 4.75 g (100+%; contained trace solvent) ofethyl-3-morpholinoproprionate as a colorless liquid. A solution of thisester (935 mg; 5 mmol) in 20 ml of Et₂ O was added to a suspension ofLiAlH₄ (400 mg; 10 mmol) in 80 ml of Et₂ O at 0° C. After stirring for30 min at 0° C., the reaction was quenched by the careful addition of0.42 ml of H₂ O followed by 0.42 ml of 15% NaOH and 1.26 ml of H₂ O.MgSO₄ was added and the suspension was filtered and concentrated toafford 531 mg (73%) of Compound 201a as a colorless liquid.

(b) Compound 201b ##STR388##

Compounds 172 and 201a were reacted by a method analogous to thatdescribed in Example 176 to give Compound 201b.

(c) Compound 201c ##STR389##

Compound 201b was converted into Compound 201c (white foam) by themethod described for Compound 177.

(d) Compound 201d ##STR390##

Compound 201c was converted to the title Compound 201d (white solid) bythe method described in Example 21. mp 122°-124° C.; [α]_(D) =-4.7° (c0.30, MeOH). Mass Spec. FAB+ions: M+H=687. Analysis calc. for C₃₇ H₅₈ N₄O₈ ·0.39H₂ O:

C, 64.05; H, 8.54; N, 8.07; Found: C, 64.10; H, 8.50; N, 8.02.

EXAMPLE 202

Preparation of [[1R*,2S*(2S*,3R*)], N² -(R*)]-N²-[(2,3-Dihydroxypropoxy)carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide(Compound 202e)

(a) Compound 202a ##STR391##

(R)-2,2-Dimethyl-1,3-dioxolane-4-methanol was converted to Compound 202a(pale yellow oil) by a method analogous to that of Example 161d.

(b) Compound 202b ##STR392##

Compound 202a and valine methyl ester hydrochloride were reacted by amethod analogous to that described for Example 161e to give Compound202b (yellow oil).

(c) Compound 202c ##STR393##

Crude Compound 202b was dissolved in a solution of glacial HOAc (10 mL)and H₂ O (2.50 mL) and heated at 40°-45° C. in an oil bath for 3 h.Volatiles were removed in vacuo to afford an orange oil, which waschromatographed on silica gel (100 mL) using a gradient from 1:1hexane:EtOAc to 100% EtOAc as eluent to afford Compound 202c (0.552 g,74% over 2 steps) as a pale yellow oil.

(d) Compound 202d ##STR394##

Compound 202c was converted to Compound 202d (white solid) by a methodanalogous to that used for the preparation of Compound 70c (THF used assolvent).

(e) Compound 202e ##STR395##

Compounds 54 and 202d were reacted by a method analogous to thatdescribed for Compound 55 (2 eq. N-methylmorpholine added; DMF onlyused) to give the title Compound 202e. This material was purified bypreparative HPLC on a Waters Delta Prep 4000, with a Waters Novapak C-18(6 μm particle size; 30×300 mm) column using as eluent a gradient from50:50 A:B to 100% A (A=90:10:0.05 MeOH:H₂ O:TFA; B=90:10:0.05 H₂O:MeOH:TFA) to give 47 mg (21%) of pure Compound 202e as a white powder.m.p.=167°-170° C.; [α]_(D) =-15.9° (c=0.23; MeOH) High resolution MS(FAB): Calculated (M+H)⁺ (for C₃₄ H₅₃ O₉ N₄)=661.3813; Observed (M+H)⁺=661.3798 Δ=2.3 ppm

EXAMPLE 203

Preparation of[1R*,2S*(2S*,3R*)1-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[[2-(phenylamino)ethoxy]carbonyl]-L-valinamide (Compound 203e)

(a) Compound 203a ##STR396##

2-Anilinoethanol, benzaldehyde and NaCNBH₃ were reacted by a methodanalogous to that of Example 126 (MeOH/1% HOAc used) to give Compound203a (clear oil).

(b) Compound 203b ##STR397##

Compound 203a was converted to Compound 203b (yellow oil whichsolidified upon standing) by a method analogous to that described inExample 161d.

(c) Compound 203c ##STR398##

Compounds 203b and 61 were reacted by a method analogous to thatdescribed in Example 161e to give 238 mg of Compound 203c (white solid).

(d) Compound 203d ##STR399##

Compound 203c was converted into Compound 203d (white solid) by a methodanalogous to that described in Example 21.

(e) Compound 203e ##STR400##

Compound 203d was converted into the title Compound 203e (white solid)by a method analogous to that of Example 2. mp 162°-167° C. ("softening"at 150°-162° C.); [α]_(D) =-15.5° (c=0.69, MeOH) Mass spectrum (FAB):706 (M+H⁺) Analysis calculated for C₃₉ H₅₅ O₇ N₅ ·1.85H₂ O:

C, 63.37 H, 8.00 N, 9.47 Found: C, 63.32 H, 7.91 N, 9.52

EXAMPLE 204

Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[[1,4-dioxo-4-(phenylamino)butyl]-L-valinamide (Compound 204b)

(a) Compound 204a ##STR401##

Compound 204a was prepared by a procedure analogous to that described inLiebigs Ann. Chem., 306, 326 (1899).

(b) Compound 204b ##STR402##

Compound 204b (white solid) was prepared starting from Compounds 61 and204a by a two-step method analogous to that used for the conversion ofCompound 48 to Compound 52. mp 218°-220° C. ("softening" at 210°-218°C.); [α]_(D) =-3.7° (c=0.47 , MeOH) mass spectrum (FAB): 718 (M+H⁺);Analysis calculated for C₄₀ H₅₅ O₇ N₅ ·0.94H₂ O:

C, 65.38 H, 7.80 N, 9.53 Found: C, 65.44 H, 7.65 N, 9.47.

EXAMPLE 205

Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-allothreoninamide (Compound 205b)

(a) Preparation of Cbz-L-allothreonine (Compound 205a)

Benzylchloroformate (0.35 ml; 2.3 mmol) was added to a mixture ofL-allothreonine (0.25 g; 2.1 mmol) and NaHCO₃ (435 mg; 5.18 mmol) in 2.5ml of H₂ O at RT. After 3 h, the reaction mixture was partitionedbetween Et₂ O and H₂ O. The aqueous layer was washed with Et20,acidified to pH <2 with 6N HCl, and extracted with CH₂ Cl₂. The organiclayer was dried (MgSO₄) and concentrated to afford 320 mg (63%) ofCbz-L-allothreonine.

(b) Compound 205b ##STR403##

Compounds 205a and 54 were reacted by a method analogous to thatdescribed in Example 55 (DMF only) to give the title Compound 205b(white solid). mp 155°-157° C.; [α]_(D) =-21.0° (c 0.45, MeOH). MassSpec. FAB+ions: M+H=679. Analysis calc. for C₃₇ H₅₀ N₄ O₈ ·0.61 H₂ O:

C, 64.43; H, 7.48; N, 8.12; Found C, 64.46; H, 7.35; N, 8.09.

EXAMPLE 206

Preparation of [4S-[4α,5α(4R*,5S*)]]-5-[[[[3-[(1,1-Dimethylethoxy)carbonyl]-4-[[4-[2-(phenyl-methoxy)ethoxy]phenyl]methyl]-2,2-dimethyl-5-oxazolidinyl]methyl][[2-(trimethylsilyl)ethoxy]-carbonyl]]amino]methyl]-2,2-dimethyl-4-(phenyl-methyl)-3-oxazolidinecarboxylicacid, 1,1-dimethylethyl ester (Compound 206) ##STR404##

To a mixture of Compound 172 (250 mg, 0.32 mmol), 2-benzyloxyethanol (91μl, 0.64 mmol) and Ph₃ P (167 mg, 0.64 mmol) in dry THF (0.64 ml) wasadded DEAD (100 μl, 0.64 mmol). The mixture was stirred at RT overnight.Concentration in vacuo followed by flash chromatography (hexane/EtOAc10:1 to 8:1) afforded 251 mg (86%) of Compound 206 as a white foam. ¹ HNMR (400 MHz, CDCl₃): 7.10-7.55 (m, 12H), 6.85 (m, 2H), 4.66 (s, 2H),4.02-4.38 (m, 8H), 3.85 (m, 2H), 3.20-3.60 (m, 4H), 2.70-3.05 (m, 4H),1.20-1.80 (m, 30H), 0.92 (m, 2H), 0.00 (s, 9H).

EXAMPLE 207

Preparation of[1R*,2S*(2S*,3R*)]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-(phenylmethoxy)ethoxy]phenyl]butyl][[2-(trimethyl-silyl)ethoxy]carbonyl]]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 207 ) ##STR405##

To Compound 206 (251 mg, 0,274 mmol) was added pre-cooled (10° C.) 96%formic acid (6.0 ml). The mixture was stirred at 5° C. for 20 min andthen frozen (dry ice-acetone) and lyophilized (overnight). The residuewas taken into MeOH (5 ml). To this solution was added Et₃ N (115 μl,0.822 mmol), followed by di-tert-butyldicarbonate (60 mg, 0.274 mmol).The mixture was stirred at RT overnight. Concentration in vacuo followedby flash chromatography (100% CHCl₃ to CHCl₃ --MeOH--NH₄ OH: 95:5:0.5)afforded 219 mg (97%) of Compound 207 as a white foam. ¹ H NMR (400 MHz,CD₃ OD): 7.05-7.35 (m, 12H), 6.79 (d, J=8.12, 2H), 4.55 (s, 2H), 4.12(m, 2H), 4.06 (t, J=4.70, 2H), 3.75 (t, J=4.70, 2H), 3.54-3.85 (m, 6H),3.10-3.30 (m, 2H, N--CH₂), 2.54 and 3.00 (both m, 4H), 1.25 and 1.26(both s, 18H), 0.99 (m, 2H), 0.00 (s, 9H).

EXAMPLE 208

Preparation of[1R*,2S*(2S*,3R*)]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-(2-hydroxyethoxy)phenyl]butyl][[2-(trimethylsilyl)ethoxy]carbonyl]]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 208) ##STR406##

To a solution of Compound 207 (219 mg, 0.265 mmol) in 4.0 ml of MeOH wasadded 75 mg Pd(OH)₂. The mixture was stirred under a H₂ atmosphereovernight. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure to give 195 mg of Compound 208 as acolorless oil, which was used immediately for the next Example. ¹ H NMR(400 MHz, CD₃ OD): 7.05-7.25 (m, 7H), 6.79 (d, J=7.69, 2H), 4.12(m, 2H),3.95 (t, J=4.91, 2H), 3.79 (t, J=4.91, 2H), 3.50-3.80 (m, 6H), 3.10-3.32(m, 2H), 2.52 and 3.00 (both m, 4H), 1.25 and 1.27 (both s, 18H), 0.99(t, J=8.55, 2H), 0.00 (s, 9H).

EXAMPLE 209

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-(2-hydroxyethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 209) ##STR407##

A mixture of Compound 208 (195 mg, 0.265 mmol) and solid n-Bu₄ NF·nH₂ O(208 mg, 0.795 mmol) in dry THF (1.2 ml) was heated at 50° C. for 4.0 h.After cooling to RT, Celite (1.0 g) was added and the solvent wasremoved under reduced pressure. Flash chromatography (100% CHCl₃ toCHCl₃ --MeOH--NH₄ OH: 94:6:0.6) on silica gel afforded 122 mg (76%) ofCompound 209 as a white solid. M.P.: 152°-154° C.; [α]_(D) =-2.9° (C0.49, MeOH). MS (FAB): 604⁺ (M+H)⁺. Anal. Calc. for C₃₂ H₄₉ N₃ O₈·1.16H₂ O:

C, 61.52; H, 8.28; N, 6.73. Found: C, 61.44; H, 7.90; N, 6.81.

EXAMPLE 210

Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl-4-(phenylmethoxy)-1,1-dimethylbutyl ester(Compound 210b)

(a) Compound 210a ##STR408##

Compound 210a (viscous oil) was prepared from 5-benzyloxy-2-pentanone(Jiang et al., J. Org. Chem, 48, 2001 (1983)) by a procedure analogousto that described in Example 158a.

(b) Compound 210b ##STR409##

Compound 210a was converted into Compound 210b (white solid) by athree-step procedure analogous to that used for the conversion ofCompound 149c to Compound 150 (DMF used in the coupling of thep-nitrophenyl carbonate with Compound 48). mp 139°-142° C. ("shrinkage"at 120°-135° C.); [α]_(D) =-3.4° (c 0.23, CH₃ OH). Mass Spec. (HighRes.) (M+H)⁺ =678. 4092 (Δppm=3.8)

EXAMPLE 211

Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-hydroxyphenylalanyl)-L-valinamide, fumarate (2:3) salt (Compound211c )

(a) Compound 211a ##STR410##

DL-o-Tyrosine was converted to Compound 211a (colorless solid) by amethod analogous to that described in Example 85a.

(b) Compound 211b ##STR411##

Compounds 211a and 61 were converted to Compound 211b (colorless solid)by a two-step procedure analogous to that used for the conversion ofCompound 48 to Compound 52.

(c) Compound 211c ##STR412##

Compound 211b was converted into Compound 211c (colorless solid) by amethod analogous to that described in Example 84. High Res. Mass Spec.(FAB): C₃₉ H₅₆ N₅ O₇ (M+H)⁺ =706.4180⁺ Δ=3.7 ppm. [α]_(D) =-12° (c=0.2,MeOH).

EXAMPLE 212

Preparation of[1R*,2S*(2S*,3R*)]-N-FN-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valyl]-L-serinamide,fumarate (2:3) salt (Compound 212b)

(a) Compound 212a ##STR413##

Compound 61 and N-Cbz-L-serine were converted to Compound 212a(colorless solid) by a two-step procedure analogous to that used for theconversion of Compound 48 to Compound 52.

(b) Compound 212b ##STR414##

Compound 212a was converted into Compound 212b (colorless solid) by amethod analogous to that described in Example 84. m.p. 178°-184° C. HighRes. Mass Spec. (FAB): C₃₃ H₅₂ N₅ O₇ (M+H)⁺ =30.3850⁺ ; Δ=2.7 ppm.

EXAMPLE 213

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,3-Dimethyl-1,2-dioxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 213c)

(a) Compound 213a ##STR415##

7 ml of 1N aqueous KOH was added to 600 mg (3.8 mmoles) of t-butyl ethyloxylate [J. Org. Chem, 35, 3726 (1970)] in 7 ml of MeOH. After 3 h, thereaction was evaporated to near dryness and the residue dissolved in H₂O and washed with Et₂ O. The aqueous layer was acidified to pH 1,saturated with solid NaCl and extracted with Et₂ O. The combinedextracts were washed with brine, dried (MgSO₄) and the solventevaporated to yield a colorless oil residue. Distillation (kugelrohr,165°-175° C., 50 mm) afforded 427 mg (86% yield) of Compound 213a as acolorless oil which crystallized on standing.

(b) Compound 213b ##STR416##

1 eq. of HCl/MeOH was added to Compound 128 in MeOH. Filtration andevaporation gave the hydrochloride salt which was reacted with Compound213a by a procedure analogous to that described in Example 51 to giveCompound 213b as a viscous foam.

(c) Compound 213c ##STR417##

Compound 213b was converted to Compound 213c (white solid) by aprocedure analogous to that described in Example 42. m.p. 133°-134° C.;[α]_(D) =-14.3° (c 0.96, MeOH) Mass Spec.: 556 (M+H) Anal. Calc. for C₃₁H₄₅ N₃ O₆ (555.7):

C, 67.00; H, 8.16; N, 7.56. Found: C, 66.87; H, 8.01; N, 7.37.

EXAMPLE 214

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,3-Dimethyl-1,2-dioxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 214b)

(a) Compound 214a ##STR418##

Compound 106d was converted to Compound 214a (white solid) by aprocedure analogous to that described in Example 7 (ETOH used).

(b) Compound 214b ##STR419##

Compounds 54 and 214a were reacted by a procedure analogous to thatdescribed in Example 55 (2 eq. of N-methylmorpholine was added; DMF onlyused) to give the title Compound 214b (white foam). Anal. Calc. for C₃₁H₄₇ N₃ O₆ ·1.75 H₂ O: C, 63.20; H, 8.64; N, 7.13. Found: C, 63.71; H,8.36; N, 6.62. HRMS: (M+H)⁺ =558.3533⁺

EXAMPLE 215

Preparation of[1S-(1R*,2S*)(trans)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-dimethylethyl 2,3-dihydro-2-hydroxy-1H-inden-1-yl ester(Compound 215d)

(a) Compound 215a ##STR420##

To a solution of indene (1 ml, 8.57 mmol) in CH₂ Cl₂ (2 8 mL ) was addedm-CPBA (2.1 g, 9.13 mmol). After stirring for 21.5 h, the mixture wasfiltered and the volatiles evaporated in vacuo. The resulting residuewas partitioned between CH₂ Cl₂ and saturated NaHCO₃, the aqueous layerback-extracted with CH₂ Cl₂, and the combined organic layers dried (Na₂SO₄). Evaporation in vacuo gave an oil containing Compounds 215a(i) and215a(ii) (1.9 g total) which was used in the next reaction.

(b) Compound 215b ##STR421##

To a cloudy solution of crude Compounds 215a(i) and 215a(ii) (<1.9 g,≦6.89 mmol) in MeOH (50 mL) was added NaOMe (1.9 mL, 8.31 mmol, 25% inMeOH). The solution was stirred at RT for 1 h, the volatiles removed invacuo, and the residue partitioned between EtOAc and brine. The combinedorganic layers were dried (Na₂ SO₄) and concentrated in vacuo. Theresidue was purified by flash chromatography (silica gel, 5 by 17 cm),eluting with EtOAc:CH₂ Cl₂ (3:2 then 2:1) to give Compound 215b (140 mg)as a colorless solid. A somewhat contaminated fraction of Compound 215bwas crystallized from hot EtOAc to give a further 74 mg (214 mg, 20.7%total).

(c) Compound 215c ##STR422##

Compound 215b was converted to Compound 215c by a procedure analogous tothat used for the synthesis of Compound 161d. Compound 215c wasseparated from its regioisomer by flash chromatography (silica gel, 5×10cm) eluting with Et₂ O:pentane (1:1 then 3:2).

(d) Compound 215d ##STR423##

Compounds 215c and 54 were reacted by a procedure analogous to that usedin Example 147d (DMF only used) to give Compound 215d (colorless solid).m.p. 131°-133° C.; [α]_(D) =-12.3° [c 0.20, MeOH]. MS: (CI): 620 (M+H).Anal. Calc. for C₃₅ H₄₅ N₃ O₇ ·1.42 H₂ O:

C,65.14; H,7.47; N,6.51 Found: C,65.22; H,7.10; N,6.43.

EXAMPLE 216

Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 2-amino-1,1-dimethylethyl-1,1-dimethylethyl ester (Compound 216e)

(a) Compound 216a ##STR424##

Isobutylene oxide was reacted with benzyl amine by a procedure analogousto that used in Example 4a except that MeOH at 105° C. was used (sealedtube).

(b) Compound 216b ##STR425##

Compound 216a was reacted with carbobenzyloxy chloride using a procedureanalogous to that of Example 122 (except that CH₂ Cl₂ was used and thereaction was run at RT) to give Compound 216b.

(c) Compound 216c ##STR426##

Compound 216b was converted to Compound 216c by a two-step procedureanalogous to that used for the conversion of Compound 149c to 149e (DMFwas used in coupling of p-nitrophenyl carbonate to Compound 48).

(d) Compound 216d ##STR427##

Compound 216c was converted to Compound 216d by a procedure analogous tothat of Example 54.

(e) Compound 216e ##STR428##

Compound 216d was converted to the title Compound 216e (white solid) bya procedure analogous to that of Example 21. m.p. 118°-120° C. Analysiscalculated for: C₃₀ H₄₆ N₄ O₆ ·1.12 H₂ O

C, 62.24; H, 8.40; N, 9.68. Found: C, 62.65; H, 8.19; N, 9.27.

EXAMPLE 217

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-methyl(4-methylphenyl)amino]-ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 217b)

(a) Compound 217a ##STR429##

A mixture of N-methyl-p-toluidine (3.5 g; 29 mmol) and ethylenecarbonate (4 g) was heated to 100° C. for 3 h and 150° C. for 10 h.After cooling to 0° C., 15 ml of 4N HCl was added and the resultingmixture was partitioned between CH₂ Cl₂ and 4N HCl. After adjusting thepH of the aqueous layer to ˜9 with solid K₂ CO₃, the aqueous layer wasextracted with CH₂ Cl₂, dried (MgSO₄) and concentrated to dryness. Theresidue was chromatographed on a 5×20 cm silica gel column, using 25%EtOAc/Hex as the mobile phase to afford 2.63 g (55%) of Compound 217a asa light yellow liquid.

(b) Compound 217b ##STR430##

Compound 217a and Compound 172 were reacted by a four-step procedureanalogous to that used for the conversion of Compound 172 to Compound178 to give the title Compound 217b (white solid). mp 120°-127 ° C.;[α]_(D) =-5.6° (c 0.27, MeOH). Mass Spec. FAB+ions: M+H=707 Analysiscalc. for C₄₀ H₅₈ N₄ O₇ ·1.27 H₂ O:

C, 65.83; H, 8.36; N, 7.68; Found: C, 66.05; H, 8.09; N, 7.46.

EXAMPLE 218

Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(2-hydroxyethoxy)carbonyl]-L-valinamide (Compound 218c)

(a) Compound 218a ##STR431##

Benzyloxyethanol and valine methyl ester hydrochloride were converted toCompound 218a by a two-step procedure analogous to that used for theconversion of Compound 161c to Compound 161e.

(b) Compound 218b ##STR432##

Compound 218a was converted to Compound 218b by a procedure analogous tothat of Example 2.

(c) Compound 218c ##STR433##

Compounds 218b and 54 were converted to the title Compound 218c (whitesolid) by a two-step procedure analogous to that used for the conversionof Compound 202c to Compound 202e. m.p.=174°-179° C.; [α]_(D) =-16.1° (c=0.23; MeOH) High resolution MS (FAB): Calculated (M+H)⁺ (for C₃₃ H₅₁ N₄O₈)=631.3707; Observed (M+H)⁺ =631.3709 Δ=0.3 ppm

EXAMPLE 219

Preparation of [[1R*,2S*(2S*,3R*)],N² -(S*)]-N²-[(2,3-Dihydroxypropoxy)carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]-amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-4-(phenylmethyl)propyl]-L-valinamide(Compound 219) ##STR434##

Starting from (S)-(+)-2,2 dimethyl-1,3-dioxolane-4-methanol, the titleCompound 219 (white solid) was prepared by a procedure analogous to thatused for the preparation of Compound 202e. m.p.=200°-205° C.(decomposes); [α]_(D) =3.3° (c=0.30; MeOH). High resolution MS (FAB):Calculated (M+H)⁺ (for C₃₄ H₅₃ O₉ N₄)=661.3831; Observed (M+H)⁺=661.3798 Δ=2.3 ppm

EXAMPLE 220

Preparation of[1R*,2S*(2S*,3R*)]-N2-[[(2-Benzimidazolyl)methoxy]carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-alaninamide(Compound 220d)

(a) Compound 220a ##STR435##

Compound 93a and 2-(trimethylsilyl)-ethoxymethyl chloride was convertedto Compound 220a by a procedure analogous to that of Example 93b(reaction was run at 70° C.).

(b) Compound 220b ##STR436##

Compound 220a and alanine were reacted by a two-step procedure analogousto that used for the conversion of Compound 93b to Compound 93d to giveCompound 220b.

(c) Compound 220c ##STR437##

Compound 220b in a 4M HCl/dioxane solution (23 ml) was stirred at 50° C.for 2.5 h then cooled to RT and stirred overnight. The reaction wasconcentrated and the resulting yellow foam was purified by silica gelchromatography, eluting the column with a stepwise gradient of EtOAc,EtOAc:AcOH (98:2), and EtOAc:MeOH:AcOH (78:20:2) to afford 0.498 g (70%)of Compound 220c.

(d) Compound 220d ##STR438##

Compounds 220c and 54 were reacted by a procedure analogous to that usedfor the preparation of Compound 93f to give the title Compound 220d(white solid). m.p. 106-108° C.; [α]_(D) =-1.0° (c, 0.10 MeOH). MassSpec. FAB: (M+H)⁺ @689⁺. Analysis calc. for C₃₇ H₄₈ N₆ O₇ ·0.65H₂ O:

C, 63.63; H, 6.83; N, 12.03; Found: C, 63.66; H, 7.13; N, 11.99.

EXAMPLE 221

Preparation of[1S-[[1R*,2S*(2S*,3R*)],N²,(S*)]]-N-[3-[[3-[[(1,1-Di-methylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-hydroxy-1-oxo-propyl)-L-valinamide (Compound 221) ##STR439##

Compound 61 and D-lactic acid were reacted by a two-step procedureanalogous to that used for the conversion of Compound 48 to Compound 52to give the title Compound 221 (white solid). mp 213°-219° C.; [α]_(D)=-56.8° (c 0.19, AcOH). Mass Spec. FAB+ion: M+H=615. Analysis calc. forC₃₃ H₅₀ N₄ O₈ ·1.34 H₂ O:

C, 62.04; H, 8.31; N, 8.77; Found: C, 62.02; H, 7.87; N, 8.79.

EXAMPLE 222

Preparation of [1R*, 2S*(2S*,3R*)]-N²-[[(3,4-Dihydro-4-oxo-2-quinazolidyl)methoxy1carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide(Compound 222d)

(a) Compound 222a ##STR440##

Compound 222a was prepared according to the procedure of Bergman et al.,Tetrahedron, 46, 1296 (1990).

(b) Compound 222b ##STR441##

Compound 222a and L-valine methyl ester hydrochloride were reacted by atwo-step procedure analogous to that used for the conversion of Compound161c to Compound 161e to give Compound 222b.

(c) Compound 222c ##STR442##

Compound 222b was converted to Compound 222c by a procedure analogous tothat of Example 70c.

(d) Compound 222d ##STR443##

Compounds 222c and 48 were reacted by a two-step procedure analogous tothat used for the conversion of Compound 48 to Compound 52 (noN-methylmorpholine was used in the EDCI coupling step) to give the titleCompound 222d (white solid). m.p. 105°-107° C. [α]_(D) +-1.8° (c=0.5,MeOH). High Res Mass Spectrum: (M+H)⁺ =745.3925, theoretical: (M+H)⁺=745.3925 (Δ0.0 ppm error).

EXAMPLE 223

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,3-Dihydro-3-oxo-1H-isoindol-1-yl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 223b)

(a) Compound 223a ##STR444##

To a MeOH (50 mL) solution of 2-carboxybenzaldehyde (5.0 g, 0.033 tool )in a cool water bath (˜18° C.) was added NH₃ gas for 15 min, and thesolution stirred at RT for 1 h. Aqueous NaCN (1.63 g, 0.033 mol in 50 mLH₂ O) was then added dropwise over 15 min. After 1 h, the volatiles wereconcentrated in vacuo and the resulting yellow solution was treated with6N HCl (40 mL). A precipitate formed after several mls of HCl had beenadded and the reaction slowly became homogeneous. The reaction mixturewas heated at 00° C. for 1.45 h, then placed in a cool water bath (˜18°C.). A yellow solid quickly formed and was removed by filtration,washing with H₂ O and acetone. The filtrate was allowed to stand at RTfor several days and the resulting solid was collected by filtration,washing with H₂ O and acetone to give slightly impure Compound 223a (2.2g, ˜38% yield). A portion (670 mg) of this material was crystallizedfrom hot H₂ O, washing the solid with more H₂ O and drying in vacuo togive Compound 223a (359 mg) as a colorless solid.

(b) Compound 223b ##STR445##

Compounds 223a and 54 were reacted by a procedure analogous to that ofExample 93f to give the title Compound 223b (colorless solid). m.p. dec.141°-152° C.; [α]_(D) ²⁵ =-1.2° (c 0.16, AcOH). MS: (FAB): 603 (M+H).Anal. Calc. for C₃₄ H₄₂ N₄ O₆ ·0.82 H₂ O:

C, 66.14; H, 7.12; N, 9.07 Found: C, 66.10; H, 6.88; N, 9.11.

EXAMPLE 224

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-(2-methoxyethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 224c)

(a) Compound 224a ##STR446##

To a mixture of Compound 172 (250 mg, 0.32 mmol), 2-methoxyethanol (50μl, 0.64 mmol) and PPh₃ (167 mg, 0.64 mmol) in dry THF (0.64 ml) wasadded DEAD (100 μl, 0.64 mmol). The mixture was stirred at RT overnight.Concentration in vacuo followed by flash chromatography (hexane/EtOAc10:1 to 7:1) afforded 225 mg (84%) of Compound 224a as a white foam.

(b) Compound 224b ##STR447##

To Compound 224a (225 mg, 0.267 mmol) was added pre-cooled (10° C.) 96%formic acid (5.0 ml). The mixture was stirred at 5° C. for 20 min andwas then frozen (dry ice-acetone) and lyophilized (overnight) . Theresidue was taken into MeOH (5 ml) and Et₃ N (112 μl, 0.80 mmol) wasadded followed by di-tert-butyldicarbonate (88 mg, 0.40 mmol). Themixture was stirred at RT overnight. Concentration in vacuo followed byflash chromatography (100% CHCl₃ to CHCl₃ --MeOH--NH₄ OH: 96:4:0.4)afforded 203 mg (100%) of Compound 224b as a white foam.

(c) Compound 224c ##STR448##

A mixture of Compound 224b (203 mg, 0.27 mmol) and solid n-Bu₄ NF-nH₂ O(223 mg, 0.85 mmol) in dry THF (1.3 ml ) was heated at 50° C. for 4.0 h.After cooling to RT, Celite (1.0 g) was added and the solvent wasremoved under reduced pressure. Flash chromatography (100% CHCl₃ toCHCl₃ --MeOH--NH₄ OH: 94:6:0.6) on silica gel afforded 128 mg (73%) ofthe title Compound 224c as a gel, which upon trituration with Et₂O-hexane afforded the product as a white solid. m.p.: 136°-138° C.;[α]_(D) =-2.3°, [α]Hg(436)=-6.1° , [α]Hg(365)=-14.2°, (c 0.53, MeOH).Mass Spec. (FAB): 618⁺ (M+H)⁺. Anal. Calc. for C₃₃ H₅₁ N₃ O₈ ·0.83H₂ O:C, 62.65; H, 8.39; N, 6.64. Found: C, 62.52; H, 8.12; N, 6.77.

EXAMPLE 225

Preparation of [1S-[[1R*,2S*(2S*,3R*)],N²-(R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]N²-(2-hydroxy-1-oxo-propyl)-L-valinamide (Compound 225 ) ##STR449##

Compound 61 and L-lactic acid were reacted by a two-step procedureanalogous to that used for the conversion of Compound 48 to Compound 52to give the title Compound 225 (white solid). m.p. 210°-214° C.; [α]_(D)=-24.8° (c 0.31, MeOH). Mass Spec. (FAB+ion): M+H=615. Analysis calc.for C₃₃ H₅₀ N₄ O₈ ·1.00 H₂ O:

C, 62.63; H, 8.28; N, 8.85; Found: C, 62.37; H, 7.84; N, 8.74.

EXAMPLE 226

Preparation of[1S-[1S*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(4-[2-(4-morpholinyl)-2-oxo-ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 226b)

(a) Compound 226a ##STR450##

NaH (48 mg, 60% dispersion in mineral oil, 1.2 mmol) was washed twicewith hexane and suspended in 1.0 ml of dry DMF. The suspension wascooled to 0° C. and a solution of Compound 175c (280 mg, 1.0 mmol) in1.5 ml of dry DMF was added. The mixture was stirred at 0° C. for 30 minand then 4-(2-bromoacetyl)morpholine (J. Med. Chem., 35, 1685 (1992);270 mg, 1.3 mmol) was added in one portion, followed by n-Bu₄ NI (185mg, 0.5 mmol). The resulting mixture was stirred at RT overnight. Aftercooling to 10° C., H₂ O was added and the mixture extracted with EtOAc.The combined extracts were washed with H₂ O and brine, dried (NaHCO₃)and concentrated in vacuo to give a crude product which was purified byflash chromatography (hexane-EtOAc: 1:1 to 1:4) on silica gel to give392 mg (96%) of Compound 226a as a white solid.

(b) Compound 226b ##STR451##

A mixture of Compounds 226a (407 mg, 1.0 mmol) and 16b (280 mg, 1.0mmol) in 1.0 ml of dry DMF was heated at 100° C. for 4.0 h.Concentration in vacuo followed by flash chromatography (CHCl₃--MeOH--NH₄ OH: 98:2:0.2 to 95:5:0.5) on silica gel afforded 501 mg(73%) of Compound 226b as a white solid. m.p. 118°-120° C.; [α]_(D)=-4.7°, [α]₃₆₅(Hg) =-23.6°(c 1.0, MeOH). Mass Spec. (FAB): 687⁺ (M+H)⁺.Anal. Calc. for C₃₆ H₅₄ N₄ O₉ ·0.30H₂ O:

C, 62.46; H, 7.95; N, 8.09. Found: C, 62.46; H, 7.91; N, 8.28.

EXAMPLE 227

Preparation of[1S-(1R*,2S*),(R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 2,3-dihydroxy-1,1-dimethylpropyl 1,1-dimethylethyl ester (Compound227c)

(a) Compound 227a ##STR452##

Methyl (S)-(-)-2,2-dimethyl-1,3-dioxolane-4-carboxylate was converted toCompound 227a by a procedure analogous to that of Example 158a.

(b) Compound 237b ##STR453##

Compound 227a was converted to Compound 227b by a three-step procedureanalogous to that used for the conversion of Compound 149c to Compound150 (DMF was used in the coupling of the p-nitrophenyl carbonate withCompound 48).

(c) Compound 227c ##STR454##

Compound 227b was converted to Compound 227c (white solid) by aprocedure analogous to that of Example 202c. m.p. 104°-105° C. High ResMass Spectrum: (M+H)⁺ =590.3463, theoretical: (M+H)⁺ =590.3441 (Δ4 ppmerror).

EXAMPLE 228

Preparation of[1S-(1R*,2S*),(S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 2,3-dihydroxy-1,1-dimethylpropyl1,1-dimethylethyl ester (Compound228) ##STR455##

Methyl (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate was converted tothe title Compound 228 (white solid) by a procedure analogous to thatused for the synthesis of Compound 227c. m.p. 69°-72° C.; [α]_(D) =-6.0°(c=0.2, CD₃ OD) Analysis Calculated for:C₃₁ H₄₇ N₃ O₈ ·1.03 H₂ O

C, 61.20; H, 8.13; N, 6.91. Found: C, 61.26; H, 7.93; N, 6.85.

EXAMPLE 229

Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 4-hydroxy-1,1-dimethyl-butyl 1,1-dimethylethyl ester (Compound229) ##STR456##

Compound 210b was converted to the title Compound 229 (white solid) by aprocedure analogous to that of Example 2. m.p. 80°-84° C.; [α]D₌₋₂.6 °(c 0.2, CH₃ OH). High Res Mass Spec (M+H)⁺ =588.3649 (Δppm=1.2) Analysiscalc. for C₃₂ H₄₉ N₃ O₇ ·2.69H₂ O: Calculated C, 60.42; H, 8.61; N,6.60; Found: C, 60.46; H, 8.22; N, 6.56.

EXAMPLE 230

Preparation of[1S-(1R*,2S*),(R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 2,3-dihydroxypropyl 1,1-dimethylethyl ester (Compound 230)##STR457##

(R)-2,2-Dimethyl-1,3-dioxolane-4-methanol was converted to the titleCompound 230 (white solid) by a three-step procedure analogous to thatused for the conversion of Compound 149c to Compound 150 (DMF was usedin the coupling of the p-nitrophenyl carbonate with Compound 48).

m.p.=151°-154° C. (decomposes); [α]_(D) =-5.3° (c=0.30; MeOH).

High resolution MS (FAB): Calculated (M+H)⁺ (for C₂₉ H₄₄ O₈N₃)=562.3128; Observed (M+H)⁺ =562.3147 Δ=3.4 ppm

Analysis for C₂₉ H₄₃ N₃ O₈.1.31 H₂ O: Calculated: C, 59.51; H, 7.86; N,7.48 Found: C, 59.19; H, 7.47; N, 7.18.

EXAMPLE 231 Preparation of [1S-(1R*,2S*),(S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 2,3-dihydroxypropyl 1,1-dimethylethyl ester (Compound 231)##STR458##

(S)-2,2-Dimethyl-1,3-dioxolane-4-methanol was converted to the titleCompound 231 (white solid) by a three-step procedure analogous to thatused for the conversion of Compound 149c to Compound 150 (DMF was usedin the coupling of the p-nitrophenyl carbonate with Compound 48).

m.p.=157°-160° C.; [α]_(D) =-8.7° (c=0.31; MeOH)

High resolution MS (FAB): Calculated (M+H)⁺ (for C₂₉ H₄₄ O₈N₃)=562.3128; Observed (M+H)⁺ =562.3127; Δ=0.2 ppm

Analysis for C₂₉ H₄₃ N₃ O₈.0.45 H₂ O: Calculated: C, 61.13; H, 7.77; N,7.38 Found: C, 60.94; H, 7.62; N, 7.57

EXAMPLE 232 Preparation of [1S-(1R*, 2S*),(R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylpropyl 2-hydroxy-1,1-dimethylpropyl ester (Compound232d)

(a) Compound 232a ##STR459##

To a solution of 0.5 g (0.48 ml; 4.23 mmol) of (S)-Ethyl lactate in 8.5ml of CH₂ Cl₂ at 0° C. was added 1.13 ml (1.2 eq; 5.07 mmol) of2,6-di-t-butylpyridine followed by 1.16 ml (1.2 eq; 5.07 mmol) oft-butyldimethylsilyl triflate. After 1 h at 0° C., Et₂ O and 1N HCl wereadded and the organic layer washed with H₂ O, saturated NaHCO₃, andbrine. The extracts were dried=(MgSO₄) and evaporated in vacuo to give acrude liquid which was purified by flash chromatography (25 mm×7";elution with 2% EtOAc/Hexanes then 5% EtOAc/Hexanes) to give 0.89 g(90%) of Compound 232a as a colorless liquid.

(b) Compound 232b ##STR460##

Compound 232a was converted to Compound 232b by a procedure analogous tothat used in Example 149c.

(c) Compound 232c ##STR461##

Compound 232b was converted to Compound 232c by a two-step procedureanalogous to that used for the conversion of Compound 147b(i) toCompound 147d.

(d) Compound 232d ##STR462##

Compound 232c was converted to Compound 232d (white solid) by aprocedure analogous to that of Example 162.

m.p. 129°-131° C. (softens at 90° C.); [α]_(D) =-20.9° (c 0.32, MeOH).

Mass Spec.: FAB+ions: M+H=574.

Analysis calc. for C₃₁ H₄₇ N₃ O₇.0.15 H₂ O: C, 64.59; H, 8.27; N, 7.29;Found: C, 64.47; H, 8.25; N, 7.41.

EXAMPLE 233 Preparation of [1S-[1R*, 2S* (2S*, 3R*)]]-[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(4-hydroxyphenyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 2-hydroxy-1,1-dimethylethyl ester (Compound 233c)

(a) Compound 233a ##STR463##

Compounds 19 and 161d were reacted by a procedure analogous to that ofExample 143 (i-Pr₂ NEt and DMF were used) to give Compound 233a.

(b) Compound 233b ##STR464##

Compound 233a was converted to Compound 233b by a procedure analogous tothat of Example 162.

(c) Compound 233c ##STR465##

Compound 233b was converted to Compound 233c (white solid) in 28% yieldby a procedure analogous to that of Example 21.

m.p. 135°-137° C.; [α]D=-4.9° (c 0.55, MeOH).

MS: (M+H)⁺ 576.3290⁺ (High res).

Anal. Calc for C₃₀ H₄₅ N₃ O₈ : C, 62.59; H, 7.88; N, 7.30. Found: C,62.20; H, 7.86; N, 7.38.

EXAMPLE 234 Preparation of [1S-[1R*,2S*(2S*,3R*),(R*)]]-[3-[[3-[[3,3-Dimethyl-2-(formylamino)-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 234c)

(a) Compound 234a ##STR466##

To a mixture of Compound 88b (286 mg, 0.414 mmol) and i-Pr₂ NEt (94 μl,0.538 mmol) in 2.5 ml of dry DMF at 0° C. was added9-fluorenylmethyl-chloroformate (124 mg, 0.48 mmol). The mixture wasstirred at 0° C. for 1.0 hr and H₂ O was added. The mixture wasextracted with EtOAc and the extracts were washed with sat'd NaHCO₃ andbrine and dried over Na₂ SO₄. Concentration in vacuo followed by flashchromatography (hexane/EtOAc 4:1 to 1:1) on a silica gel column afforded341 mg (90%) of Compound 234a as a white solid.

TLC(SiO₂)Rf=0.51.

(CHCl₃ - MeOH 95:5 - PMA).

(b) Compound 234b ##STR467##

A mixture of Compound 234a (341 mg, 0.374 mmol), 1,4-cyclohexadiene (356μl) and 10% Pd-C (40 mg) in 11 ml of EtOH was stirred under a H₂atmosphere for 2 h. An additional 25 mg of 10% Pd-C was added after 2and 4 h. After 6 h total, the catalyst was removed by filtration througha short pad of Celite. 90 μl of HOAc was added to the filtrate and themixture was evaporated to dryness to yield 308 mg of the amine acetatesalt as a white solid.

Formic acetic anhydride was prepared by addition of 46.3 μl of HCO₂ H to133 μl of ice-cooled Ac₂ O. The solution was then stirred at 50° C. for2 h. This material dissolved in 1 ml of dry THF was added to anice-cooled solution of 308 mg of the amine acetate salt in 2.5 ml of dryTHF. The mixture was stirred at 0° C. for 1.0 h and then at RT for 15min. The reaction mixture was partitioned between H₂ O and EtOAc and theorganic extracts were washed with brine and dried (Na₂ SO₄).Concentration in vacuo followedby purification by prep HPLC (Nova-Pak HRsilica 60 Å) with 60% EtOAc in hexane as eluent, afforded 123 mg (41%for two steps) of Compound 234b as a white solid.

TLC(SiO₂)R_(f) =0.17.

(CHCl₃ -MeOH 95:5 - PMA).

(c) Compound 234c ##STR468##

To a solution of Compound 234b (123 mg, 0.152 mmol) in 2.7 ml of dry CH₂Cl₂ was added piperidine (132 μl, 1.34 mmol). The mixture was stirred atRT for 1.5 h. Concentration in vacuo followed by flash chromatography(CHCl₃ -MeOH-NH₄ OH: 99:1:0.1 to 92:8:0.8) on silica gel gave, aftertrituration with CHCl₃ -hexane, 84 mg (94%) of the title Compound 234cas a white solid.

m.p.: 166°-168° C.; [α]_(D) =-23.8°, [α]₄₃₆(Hg) =-54.8° (c 0.21, MeOH).

Mass Spec. (FAB): 585⁺ (M+H)⁺.

Anal. Calc. for C₃₂ H₄₉ N₄ O₆.0.34H₂ O: C, 64.93; H, 8.46; N, 9.47.Found: C, 64.99; H, 8.20; N, 9.41.

EXAMPLE 235 Preparation of[1S-[1R*,2S*[2S*,3R*(E)]]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-6-(4-hydroxyphenyl)-5-hexenyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 235e)

(a) Compound 235a ##STR469##

Compound 235a was prepared according to the procedure of Oppolzer etal., Tetrahedron Lett., 30 (44), 6009 (1989).

(b) Compound 235b ##STR470##

To a solution of n-BuLi (4.4 ml; 11.0 mmol; 2.5M in hexanes) in 25 ml ofdry THF cooled at -78° C. was added a solution of Compound 235a (3.77 g;10.0 mmol) in 15 ml of dry THF. The mixture was stirred at -78° C. for 1h, followed by addition of a solution of4-t-butyldiphenylsilyloxycinnamyl bromide (Young et al., J. Med. Chem.,35, 1702 (1992)); 6.8 g, 15.0 mmol) in 10 ml of 1:1 THF-HMPA, dropwiseover 10 min. n-Bu₄ NI (200 mg) was then added and the reaction waswarmed from -78° C. to RT over 2 hours. The reaction mixture was cooledback to -20° C. and H₂ O was added. The mixture was extracted with EtOAcand the combined extracts washed with H₂ O and brine and dried overMgSO₄. Concentration in vacuo gave an oily residue which was purified byflash chromatography (10:1 hexane-chloroform to 100% chloroform) onsilica gel to afford 5.2 g (69%) of Compound 235b as a colorless oilwhich solidified upon standing.

(c) Compound 235c ##STR471##

To a solution of Compound 235b (14.7 g, 19.7 mmol) in 280 ml of THF and125 ml of DME was added a solution of 1.0 N HCl (125 ml). Thehomogeneous mixture was then heated at 40° C. overnight. H₂ O (200 ml)was added and the pH was adjusted to 12 with 6N KOH. The mixture wasextracted with EtOAc and the combined organic extracts washed with H₂ O,saturated NaHCO₃, brine and dried over Na₂ SO₄. Removal of solvent underreduced pressure afforded 13.9 g of crude amine as an off-white foamwhich was used without further purification.

To the suspension of the crude amine (13.9 g) in 85 ml of dry CH₃ CNcooled at 0° C. was added di-t-butyl dicarbonate (7.7 g, 32.5 mmol). Thereaction mixture was stirred at RT overnight. The solvent was removedunder reduced pressure and the residue was purified by flashchromatography (hexane-EtOAc: 4:1) on silica gel to afford 13.7 g of theN-Boc carbamate as an off-white foam.

To a solution of LiOH.H₂ O (1.5 g, 36.8 mmol) in H₂ O (36 ml) cooled at0° C. was added a solution of 30% H₂ O₂ (11.3 ml, 110 mmol). The mixturewas stirred at 0° C. for 1 h and added at 0° C. to a solution of theabove prepared N-Boc carbamate (13.7 g, 18.4 mmol) in 380 ml of 3:1THF-H₂ O. The reaction mixture was stirred at 0° C. for 15 min and asolution of 1.5N Na₂ SO₃ (85 ml) was added. After stirring for another30 min, the mixture was acidified to pH=2 with 3N HCl and extracted withEtOAc. The combined extracts were washed with brine and dried over Na₂SO₄. Concentration in vacuo followed by flash chromatography (CHCl₃-MeOH-AcOH: 95:5:1) on silica gel afforded 7.74 g (77%) of Compound 235cas a white solid.

(d) Compound 235d ##STR472##

Compound 235c was converted to Compound 235d by a procedure analogous tothat used for the preparation of Compound 175b.

(e) Compound 235e ##STR473##

Compounds 235d and 16b were reacted by a procedure analogous to thatused for the synthesis of Compound 4b to give the title Compound 235e(off-white solid).

m.p.: 110°-112° C.; [α]_(D) =+1.6° (c 0.25, MeOH).

Mass Spec. (FAB): 586⁺ (M+H)⁺.

Anal. Calc. for C₃₂ H₄₇ N₃ O₇.0.82 H₂ O: C, 64.00; H, 8.16; N, 7.00.Found: C, 64.15; H, 8.05; N, 6.85.

EXAMPLE 236 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 2-(formylamino)-1,1-dimethylethyl 1,1-dimethylethyl ester(Compound 236b)

(a) Compound 236a ##STR474##

Compound 216d was reacted with formylacetic anhydride in THF by aprocedure analogous to that of Example 129 to give Compound 236a.

(b) Compound 236b ##STR475##

Compound 236a was converted to the title Compound 236b (white solid) bya procedure analogous to that of Example 21. The final product waspurified by reverse phase HPLC (19×300 mm C18 column) eluted with acontinuous gradient (30:70 A:B to 80:20 A:B; A=90% CH₃ OH/H₂ O+0.05%TFA; B=10% CH₃ OH/H₂ O+0.05% TFA). The resulting foamy white solid waslyophlized from CH₃ OH/H₂ O.

m.p. 78°-81° C.; [α]_(D) =-7.8° (C=0.2, CH₃ OH).

Analysis calculated for:C₃₁ H₄₆ N₄ O₇.1.89 H₂ O C, 59.98; H, 8.08; N,9.02. Found: C, 60.45; H, 7.73; N, 8.55.

EXAMPLE 237 Preparation of[1S-[1R*,2S*[2S*,3R*(trans)]]]-[3-[[3-[[(2,3-Dihydro-2-hydroxv-1H-inden-1-yl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 237c)

(a) Compounds 237a (i) and 237a (ii) ##STR476##

To a mixture of NaBH₄ (230 mg, 6.08 mmol) in aqueous EtOH (30 mL, 95% )at 0° C. was added 1-carboethoxy-2-indanone (0.62 g, 3.03 mmol, preparedas in J. Chem. Soc., 121, 1562-1571 (1922)). After stirring for 1 h,solid NH₄ Cl (140 mg, 2.61 mmol) was added and the mixture was broughtto RT. More solid NH₄ Cl (440 mg, 8.22 mmol) was added after 2 h,followed by NaBH₄ (59 mg, 1.56 mmol). Further amounts of NH₄ Cl (995 mgover 11.5 h), and then NaBH₄ (573 mg over 11.5 h), were addedperiodically over the next 11.5 h. The mixture was evaporated in vacuo,the resulting residue suspended in saturated NH₄ Cl and extracted withEtOAc. The combined organic layers were dried (Na₂ SO₄) and evaporatedin vacuo to an oil which was purified by flash chromatography (silicagel, 3 by 20 cm), eluting with EtOAc:CH₂ Cl₂ (1, 2, 3, and then 5%EtOAc) to give Compounds 237a(i) and 237a(ii) (350 mg, 3:2 ratio by ¹ HNMR, 56% yield) as a colorless oil.

(b) Compound 237b ##STR477##

To neat Compounds 237a(i) and 237a(ii) (350 mg, 1.70 mmol) was added INNaOH (3 mL, 3 mmol). After 1.5 h, the solution was brought to pH 1 with1N HCl. The resulting solution was extracted with Et₂ O, the combinedorganic layers dried over Na₂ SO₄ and concentrated in vacuo to give anoily solid. This residue was dissolved in hot EtOAc, diluted with hotpentane and allowed to slowly cool. After storing overnight at -20° C.,the solid was triturated twice with cold pentane/EtOAc (4:1) to giveafter drying in vacuo Compound 237b (219 mg, 72% yield) as a slightlyorange colored solid.

(c) Compound 237c ##STR478##

Compounds 237b and 54 were reacted by a procedure analogous to that ofExample 55 (DMF only used) to give the title Compound 237c (colorlesssolid).

m.p. (shrink 141° C.) dec. 161°-165° C.; [α]_(D) =+10°-7° (c 0.41,HOAc).

MS: (CI): 604 (M+H).

Anal. Calc. for C₃₅ H₄₅ N₃ O₆.0.51 H₂ O C, 68.58; H, 7.57; N, 6.86Found: C, 68.53; H, 7.41; N, 6.91

EXAMPLE 238 Preparation of[1S-[1R*,2*(2S*,3R*)]]-[3-[[3-[[2-[3-(2-Benzimidazoly)propoxy]-3,3-dimethyl-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 238e)

(a) Compound 238a ##STR479##

The triflate of 4-pentene-1-ol was prepared by the addition of 5.5 ml(33 mmol) of triflic anhydride in 50 ml of CH₂ Cl₂, over a period of 1hr, to a solution of 3.1 g (30 mmol) of 4-pentene-1-ol and 3.6 ml (45mmol) of pyridine in 150 ml of CH₂ Cl₂, at -10° C. After the additionwas complete, the cold reaction was washed twice with 1N HCl, twice withbrine, sat NaHCO₃, and twice with brine. The solution was dried (MgSO₄)and the solvent removed to yield 6.6 g (assumed 30 mmol, 100%) of thetriflate as a pale yellow oil. This material was used immediately in thenext step.

To a suspension of 1.7 g (15 mmol) of 35% KH suspension (hexane washed)in 50 ml of THF, at RT was added dropwise a solution of 4.8 g (13.3mmoles) of Compound 106a in 25 ml of THF. After 2 h the solution was icecooled and diluted with 75 ml of DMF. To this solution was added asolution of the freshly prepared pre-cooled (-78° C.) 4-pentene-1-oltriflate in 10 ml of THF. After stirring for 0.5 h at 0° C. and RT for 1h, the reaction was diluted with brine and extracted twice with Et₂ O.The extracts were washed with brine, dried (MgSO₄), the solvent removedand the resulting oil purified by flash chromatography on a 400 cccolumn of silica gel (elution with 25% CH₂ Cl₂ /hexane) to afford 2.9 g(51%) of Compound 238a as a colorless oil.

(b) Compound 238b ##STR480##

A solution of 1.7 g (4 mmoles) of Compound 238a, 1.9 g (12 mmoles) ofKMnO₄, and 75 mg of n-Bu₄ NBr in 20 ml of toluene, 20 ml of H₂ O and 4ml of HOAc was stirred for 2 h. To the resulting slurry was added sat.NaHSO₃ with stirring until the reaction became colorless. The suspensionwas extracted with EtOAc and the combined extracts washed with brine,dried (MgSO₄) and the solvent removed to yield a crude product which waspurified by flash chromatography on a 125 cc column of silica gel(elution with 25% EtOAc/hexane) to afford 1.1 g (62%) of Compound 238bas a colorless oil.

(c) Compound 238c ##STR481##

To a solution of 1.0 g (2.2 mmol) of Compound 238b and 0.42 ml (3 mmol)of Et₃ N in 10 ml of THF, at -10° C. was added dropwise 0.32 ml (2.5mmol) of i-butylchloroformate. After 0.5 h, a solution of 270 mg (2.5mmol) of o-phenylenediamine in 5 ml of THF was then added. After 1.5 hat -10° C., the reaction was diluted with EtOAc and washed with H₂ O,sat. NaHCO₃, and brine, dried (MgSO₄) and the solvent removed to give1.3 g of a white foam. This material was dissolved in 25 ml of HOAc andheated at 65° C. for 3.5 hr. After cooling, the solution was evaporatedto dryness. The residue was taken into EtOAc and washed with sat NaHCO₃and brine. After drying (MgSO₄), removal of solvent gave a residue whichwas purified by flash chromatography on a 125 cc column of silica gel(elution with 100% EtOAc) to give 266 mg (44%) of Compound 238c as asolid foam.

(d) ComDound 238d ##STR482##

75 mg (0.27 mmol) of Compound 238c was converted to the correspondingaldehyde by a procedure analogous to that of Example 191c. To 50 mg ofthe intermediate aldehyde in 0.5 ml of THF and 0.9 ml (1.8 mmoles) of a2M THF solution of 2-methyl-2-butene was added dropwise a solution of 23mg (0.2 mmol) of sodium chlorite (80%) in 0.5 ml of pH 3.95 acetatebuffer. After 1 h, the reaction was evaporated to dryness and theresidue taken into 1 ml of H₂ O saturated with solid NaCl and the pHadjusted to 5.0 by the addition of HOAc. After extraction with EtOAc,the combined organic layers were washed once with minimal brine, dried(MgSO₄), and the solvent removed to give a crude product which waspurified by flash chromatography on a 15 cc column of silica gel(elution with 5%, 10% and 20% MeOH/CHCl₃) to afford 35 mg (45%) ofCompound 238d as a white solid.

(e) Comoound 238e ##STR483##

Compounds 238d and 54 were reacted by a procedure analogous to that ofExample 93f to give the title Compound 238e (solid foam) as a 1:1mixture of diastereomers.

High Res Mass Spec.: (M+H)⁺ =716.4375; calc. 716.4387.

Calc. for C₄₁ H₅₇ N₅ O₆.H₂ O (733.9): C, 67.09; H, 8.10; N, 9.54. Found:C, 67.01; H, 8.00; N, 9.21.

EXAMPLE 239 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(5,5-Dimethyl-2-oxo-4-oxazolidinyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A (Compound 239d)

(a) Compound 239a ##STR484##

Dimethylacrylic acid and sodium tungstate were suspended in H₂ O (0.67ml/g acid) the pH of which was adjusted to 6.5 with aq. NaOH. At RT, 35%aq. H₂ O₂ (4.1 mol eq.) was added dropwise maintaining the pH withadditional aq. NaOH. After the addition was complete, the reaction wasstirred for 1 h at 40° C. at which time Na₂ SO₃ was added to destroyexcess peroxide. Benzylamine was added (1.2 eq.) and the resultingmixture stirred at reflux for 2 h. The reaction was partiallyconcentrated and then brought to pH 6 with concentrated HCl. Thereaction was cooled to RT and the solid product Compound 239a filteredoff and washed with cold H₂ O and EtOH (28%).

(b) Compound 239b ##STR485##

Compound 239a was stirred in MeOH (10 ml/g) along with 10% Pd/C under aH₂ atmosphere for 1 h (35° C.). After filtering off the catalyst, thereaction was partially concentrated and then cooled to 0° C. Acetone (7ml/g Compound 239a) was added and the resulting solid Compound 239bfiltered and washed with acetone (100%).

(c) Compound 239c ##STR486##

To a solution of Compound 239b (1.33 g, 10.0 mmol) in 12.5% aq. KOH (37ml) cooled at 0° C. was added a solution of phosgene (1.93M) in toluene(11.7 ml). The mixtureswas stirred at 0° C. for 1.0 h and the toluenelayer was separated. The aqueous layer was washed with Et₂ O, acidifiedto pH=3 with 3N HCl and concentrated in vacuo to afford a solid residue.This residue was extracted into hot methanol (200 ml) and the solidremoved by filtration. The filtrate was concentrated in vacuo and thenpartitioned between 5% KHSO₄ and EtOAc. The aqueous layer was extractedwith hot EtOAc and the combined organic layers were dried (Na₂ SO₄) andconcentrated to afford 1.38 g (87%) of Compound 239c as an off-whitesolid.

(d) Compound 239d ##STR487##

Compounds 54 and 239c were reacted by a procedure analogous to that ofExample 93f to give Compound 239d along with its diastereomer Compound240 as a 1:1 mixture. HPLC purification (S-10 C18; 120 Å ODS; MeOH-H₂O-TFA 60:40:0.1) gave the title Compound 239d (white solid) as theslower moving isomer.

m.p. 108°-110° C.; [α]_(D) -5.0° (c 0.2, MeOH).

Mass Spec. (FAB): 585⁺ (M+H)⁺.

Analysis Calc. for C₃₁ H₄₄ N₄ O₇ : C, 63.68; H, 7.58; N, 9.51. Found: C,63.75; H, 7.79; N, 9.51.

EXAMPLE 240 Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(5.5-Dimethyl-2-oxo-4-oxazolidinyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer B (Compound 240) ##STR488##

Compound 240 (white solid) was isolated by preparative HPLC (the fastermoving isomer) as described in Example 239.

m.p. 120°-122° C.; [α]_(D) =-18.3° (c 0.25, MeOH).

Mass Spec. (FAB): 585⁺ (M+H)⁺.

Analysis Calc. for C₃₁ H₄₄ N₄ O₇.1.08H₂ O: C, 61.63; H, 7.70; N, 9.27.Found: C, 61.70; H, 7.62; N, 9.20.

EXAMPLE 241 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-dimethylethyl-2-hydroxyethyl ester (Compound 241c)

(a) Compound 241a ##STR489##

Benzyloxyethanol was converted to Compound 241a by a procedure analogousto that of Example 161c.

(b) Compound 241b ##STR490##

Compound 241a was converted to Compound 241b by a procedure analogous tothat of Example 7.

(c) Compound 241c ##STR491##

Compounds 241b and 48 were converted to the title Compound 241c (whitesolid) by a three-step procedure analogous to that used for theconversion of Compound 149c to Compound 150 (DMF was used as the solventin the coupling reaction of Compound 48 with the p-nitrophenyl carbonateof Compound 241b).

m.p.=168°-172° C.; [α]_(D) =-8.3° (c=0.32; MeOH)

MS (FAB): (M+H)⁺ =532;

Elemental Analysis: (for C₂₈ H₄₁ N₃ O₇.0.27 H₂ O) Calculated: C, 62.68;H, 7.80; N, 7.83 Found: C, 62.69; H, 7.68; N, 7.82.

EXAMPLE 242 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[4-[4-[(2-Benzoxazolyl)methoxylphenyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxybutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 242) ##STR492##

Compounds 171a and 172 were reacted by a four-step procedure analogousto that used for the conversion of Compound 172 to Compound 178 to givethe title Compound 242 (white solid).

mp 145°-150° C.; [α]₃₆₅ =-21.7° (c 0.27, MeOH).

Mass Spec. FAB+ions: M+H=691

Analysis calc. for C₃₈ H₅₀ N₄ O₈.1.09 H₂ O: C, 64.24; H, 7.40; N, 7.89;Found: C, 64.16; H, 7.14; N, 7.97.

EXAMPLE 243 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-alaninamide (Compound 243) ##STR493##

Compound 54 and N-carbobenzyloxy-L-alanine were reacted by a procedureanalogous to that of Example 55 (DMF only used) to give the titleCompound 243 (white solid).

mp 156°-157° C., [α]_(D) =-10° (c 0.10, MeOH).

Mass Spec. IONSPRAY+ion; (M+H)⁺ =649⁺.

Analysis calc. for C₃₆ H₄₈ N₄ O₇ ·0.25H₂ O: C, 66.18; H, 7.48; N, 8.58;Found: C, 66.21; H, 7.47; N, 8.55.

EXAMPLE 244 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[3-[(2-benzoxazolyl)-propoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 244b)

(a) Compound 244a ##STR494##

A mixture of o-aminophenol (2.5 g; 23 mmol), 4-pentenoic acid (2.33 ml;23 mmol) and p-toluenesulfonic acid (150 mg) in 50 ml of toluene wasrefluxed with azeotropic removal of H₂ O for 30 hours. After cooling toRT, the reaction mixture was partitioned between EtOAc and 1N NaOH andthe organic layer washed with 1N NaOH, H₂ O and brine. After drying overMgSO₄ and decolorizing over charcoal (Darco), the organic layer wasfiltered and concentrated to afford 793 mg (20%) of the intermediate,benzoxazole-2-prop-3-ene, as a yellow liquid. Ozone was bubbled througha solution of this intermediate (492 mg; 2.8 mmol) in 13 ml of MeOH at-78° for -3 min. The reaction was stopped when starting material wasconsumed by TLC (EtOAc:Hex, 1:1). After purging with oxygen, thereaction mixture was warmed to -35° C. and 1.5 ml of H₂ O, followed byNaBH₄ (163 mg; 4.2 mmol), was added. The reaction mixture was warmed to0° C. over 1 h, at which time saturated aqueous NH₄ Cl (3 ml) was added.Most of the MeOH was removed in vacuo and the residue was partitionedbetween EtOAc and saturated aqueous NH₄ Cl. The organic layer was washedwith saturated aqueous NH₄ Cl and brine. After drying over MgSO₄ andconcentrating, the residue was chromatographed on a 2.5×5 cm silica gelcolumn using EtOAc as the mobile phase to afford 400 mg (81%) ofCompound 244a as an orange solid.

(b) Compound 244b ##STR495##

Compounds 244a and 172 were reacted by a four-step procedure analogousto that used for the conversion of Compound 172 to Compound 178 to givethe title Compound 244b (white solid).

mp 121°-126° C.; [α]₃₆₅ =-3.6° (c 0.48, MeOH).

Mass Spec. FAB+ions: M+H=719

Analysis calc. for C₄₀ H₅₄ N₄ O₈.1.28 H₂ O: C, 64.75; H, 7.68; N, 7.55;Found: C, 64.59; H, 7.43; N, 7.71.

EXAMPLE 245 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N₂-[[(1H-benzimidazol-1-yl-methyl)methylamino]carbonyl]-L-valinamide(Compound 245d)

(a) Compound 245a ##STR496##

To a 40% aqueous solution of methylamine (100 ml) cooled to 0° C. wasslowly added 2-chloromethyl benzimidazole (6.0 g, 36 mmol). After 1additional h at 0° C. the reaction was diluted with H₂ O and extractedwith CH₂ Cl₂. The combined extracts were dried (Na₂ SO₄) and the solventwas evaporated in vacuo to give a crude product which was purified on asilica column eluting with a gradient from 5 to 10% MeOH/CH₂ Cl₂ +0.1%NH₄ OH to afford 680 mg (12%) Compound 245a as a colorless solid.

(b) Compound 245b ##STR497##

Pyridine (1.19 g; 15 mmol) was added to a suspension of L-valine methylester hydrochloride (1 g; 6 mmol) in CH₂ Cl₂ at 0° C.p-Nitrophenyl-chloroformate (1.33 g; 6.6 mmol) was added and the mixturestirred at 0° C. for 2 h and at RT for 1 h. The reaction was dilutedwith EtOAc and washed with 10% KHSO₄, sat. NaHCO₃, H₂ O and brine. Theorganic layer was dried (Na₂ SO₄) and concentrated to afford 1.4 g (80%)of Compound 245b as a pale-yellow solid.

(c) Compound 245c ##STR498##

A mixture of Compound 245a (282 mg, 1.75 mmol), Compound 245b (518 mg,1.75 mmol), and Et₃ N (354 mg, 3.5 mmol) in 9 ml of dry CH₃ CN wasstirred overnight at RT. The volatiles were evaporated to give a crudeproduct which was purified on a silica column eluting with a gradientfrom 2 to 5% MeOH/CH₂ Cl₂ +0.1% NH₄ OH to afford 136 mg (24%) ofCompound 245c as a colorless solid.

(d) Compound 245d ##STR499##

Compounds 245c and 54 were reacted by a two-step procedure analogous tothat used for the conversion of Compound 70b to Compound 70d (DMF only;no N-methyl morpholine was added) to give the title Compound 245d(colorless solid).

m.p. 184°-188°C. (dec); [α]_(D) =-18.5° (c=0.25, MeOH)

High Res. Mass Spec. (FAB): (M+H)⁺ =730.4292⁺ ; C₄₀ H₅₆ N₇ O₆ Δ=1.5 ppm.

EXAMPLE 246 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-methoxycarbonyl)-3-methyl-L-valinamide (Compound 246b)

(a) Compound 246a ##STR500##

To a 0° C. solution of (L)-t-leucine (0.600 g, 4.57 mmol) in aqueousNaOH (2.80 mL of a 2.0N solution) were added in alternate portionsmethyl chloroformate (0.388 mL, 5.03 mmol) and aqueous NaOH (2.20 mL ofa 2.0N solution) over 5 min. The solution was stirred at 0° C. for 30min and for 1 h at RT. The aqueous solution was washed with Et₂ O,acidified with aqueous 3M HCl solution to pH 1 and extracted with EtOAc.The combined organic extracts were dried (Na₂ SO₄) and concentrated invacuo to give the Compound 246a (0.867 g, ≦100%) as a colorless glass,which was used in the next step without purification.

(b) Compound 246b ##STR501##

To a 0° C. solution of Compound 246a (0.094 g, 0.496 mmol) and HOBT.H₂ O(0.114 g, 0.744 mmol) in DMF (1.0 mL) was added EDC (0.095 g, 0.496mmol). The solution was stirred at 0° C. for 1 h. Compound 54 (200 mg,0.451 mmol) in 1 ml DMF was added followed by N-methyl morpholine (0.165mL, 1.50 mmol). The solution was allowed to warm to RT and and stir for36 h at which time volatiles were removed in vacuo. The residue waspartitioned between aqueous 50% NaHCO₃ and EtOAc. The combined organicextracts were washed with brine, dried (Na₂ SO₄), and concentrated invacuo to give solid, which was chromatographed on silica gel (100 mL)using a gradient from 99:1:0.1 to 90:10:1 CH₂ Cl₂ :MeOH:NH₄ OH as eluentto afford Compound 246b as a white solid (135 mg; 49%).

m.p.=153°-156° C.; [α]_(D) =-16.1° (c=0.33; MeOH) MS (FAB): (M+H)⁺ =615;

Elemental Analysis: (for C₃₃ H₅₀ N₄ O₇.1.09 H₂ O) Calculated: C, 62.48;H, 8.29; N, 8.83 Found: C, 62.48; H, 8.06; N, 8.83.

EXAMPLE 247 Preparation of [1R*, 2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl) propyl]-N²-(methoxycarbonyl)-L-valinamide (Compound 247) ##STR502##

Compound 54 and L-valine were converted into the title Compound 247(white solid) by a two-step procedure analogous to that of Example 246.

m.p. 202°-205° C.; [α]_(D) =-33.3° (C 0.06, MeOH)

Analysis Calc. for C₃₂ H₄₈ O₇ N₄. 0.28 H₂ O C, 63.44; H, 8.08; N, 9.25Found: C, 63.51; H, 8.03; N, 9.18.

EXAMPLE 248 Preparation of [1R*, 2S*, (2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N² -(1-oxopropyl)-L-valinamide (Compound 248) ##STR503##

Compound 61 and propionic acid were converted into the title Compound248 (white solid) by a two-step procedure analogous to that used for theconversion of Compound 48 to Compound 52.

m.p. 222°-225° C.; [α]_(D) =-28.5° (c 0.07, MeOH)

Analysis Calc. for C₃₂ H₅₀ O₆ N₄. 0.64 H₂ O: C, 64.95; H, 8.47; N, 9.18Found: C, 64.90; H, 8.31; N, 9.23.

EXAMPLE 249 Preparation of [1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(1H-imidazol-2-ylmethoxy)carbonyl]-L-valinamide, acetate (2:3) salt(Compound 249c)

(a) Compound 249a ##STR504##

To a solution containing 1-trityl-2-formyl imidazole (1.54 g, 4.55 mmol;J. Org. Chem., 43, 4381 (1978)) in a mixture of 12 mL of THF and 12 mLof EtOH cooled to 0° C. was added portionwise NaBH₄ (300 mg, 7.93 mmol).After 45 min at 0° C., the cold reaction mixture was quenched with pH 4phosphate buffer and extracted with CH₂ Cl₂. The combined organicextracts were washed with brine, dried (MgSO₄) and concentrated in vacuoto afford 1.47 g of Compound 249a as a waxy solid (95%, crude yield).

(b) Compound 249b ##STR505##

Compound 249a and 61 were converted into Compound 249b by a three-stepprocedure analogous to that used for the conversion of Compound 149c toCompound 150 (Et₃ N was used in the coupling of Compound 61 with thep-nitrophenyl carbonate of Compound 249a).

(c) Compound 249c ##STR506##

Compound 249b (250 mg, 0.275 mmol) was dissolved in a mixture of 3 mL ofabsolute EtOH and 12 mL of HOAc. The reaction mixture was heated at 40°C. for 3.5 h in a stoppered flask, then concentrated in vacuo andtriturated with CH₂ Cl₂ -hexanes to afford the title Compound 249c (180mg, 83% ) as a white solid.

m.p. (softens 129° C.), 135°-152° C.; [α]_(D) =+1.2° (c=0.21, MeOH).

MS (FAB): (M+H)⁺ =667⁺

Elemental Analysis: Calcd for C₃₅ H₅₀ N₆ O₇ ·1.5 C₂ H₄ O₂ ·1.8 H₂ O: C,57.82; H, 7.61; N, 10.65. Found: C, 57.77; H, 7.27; N, 11.04.

EXAMPLE 250 Preparation of [1R*,2S*(2S*,3R*)]-N₂-[3-Dihydro-3-oxo-2H-indazol-2-yl)-1-oxopropyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide(Compound 250e)

(a) Compound 250a ##STR507##

To a solution of 0.380 mg (16,5 mmol) of Na metal in 25 mL of anhydrousEtOH was added 2.01 g (15.0 mmol) of indazolinone. The resultingsuspension was heated at reflux for 15 min at which point 1.9 mL (16.5mmol) of benzyl chloride was added over 15 min. The resulting mixturewas heated at reflux for 7 h, cooled to RT, concentrated in vacuo, andthe residue diluted with 150 mL of 1N NaOH. The mixture was extractedwith Et₂ O. The aqueous layer was acidified to pH=5 with HOAc and thenextracted with Et₂ O. The Et₂ O extracts were dried (Na₂ SO₄), filtered,and concentrated in vacuo and the solid recrystallized from H₂ O/MeOH togive 990 mg (29%) of Compound 250a.

(b) Compound 250b (i) ##STR508##

To a solution of 0.253 mg (11.0 mmol) of Na metal in 20 mL of anhydrousEtOH was added 2.29 g (10.2 mmol) of Compound 250a. The mixture washeated at reflux for 15 min at which point 1.13 mL (12.0 mmol) of3-bromopropanol in 5 mL of toluene was added over 10 min. After 4 h, anadditional 0.38 mL (1.1 mmol; 21% wt in ethanol) of sodium ethoxide and0.1 mL of 3-bromopropanol were added. The mixture was heated at refluxfor 2 h, and then stirred at RT for 12 h. The cooled mixture wasconcentrated in vacuo, and the residue was diluted with 150 mL of 1NNaOH. The mixture was extracted with Et₂ O and the extracts washed withbrine dried (Na₂ SO₄), filtered, and concentrated in vacuo. Flashchromatography on silica gel (10-50% EtOAc-CH₂ Cl₂ ; then, 5% CH₃ OH-CH₂Cl₂) provided 634 mg (22%) of Compound 250a(i) [TLC Rf=0.10 (10%EtOAc-CH₂ Cl₂)] and 2 g of Compound 250b(ii) [TLC Rf=0.37 (10% EtOAc-CH₂Cl₂)].

(c) Compound 250c ##STR509##

To a solution of 200 mg (0.708 mmol) of Compound 250b(i) in 3.5 mL ofdry DMF was added 1.03 g (2.73 mmol) of pyridinium dichromate. Themixture was stirred at RT for 18 h then poured into 1:1 H₂ O/brine (100mL) and extracted with Et₂ O. The organic layer was dried (Na₂ SO₄),filtered, and evaporated in vacuo to give 130 mg (62%) of Compound 250c.

(d) Compound 250d ##STR510##

To a solution of 238 mg (0,439 mmol) of Compound 59, 130 mg (0.439 mmol)of Compound 250c, and 119 mg (0.88 mmol) of HOBT in 2.5 mL of dry DMF at0° C. was added 93 mg (0.483 mmol) of EDCI. The mixture was stirred at0° C. for 3 h and at RT for 18 h then concentrated in vacuo. The residuewas diluted with EtOAc, and washed with saturated NaHCO₃, H₂ O, andbrine. The organic layer was concentrated in vacuo, and purified byflash chromatography on silica gel [2-10% CH₃ OH/CH₂ Cl₂ with 1.0% NH₄OH] to provide 265 mg [74% yield (88% pure by HPLC)] of Compound 250d.

(e) Compound 250e ##STR511##

A solution of 185 mg (0.225 mmol) of Compound 250d in 12 mL of hot MeOHwas cooled to RT, and treated with 100 mg of 10% Pd/C. The mixture wasstirred under a H₂ atmosphere for 24 h then an additional 100 mg of 10%Pd/C was added and the mixture was stirred under a H₂ atmosphere foranother 12 h. The mixture was filtered, rinsed with hot MeOH, andevaporated in vacuo. Flash chromatography of the residue on silica gel[2% CH₃ OH/CH₂ Cl₂, then 3-10% CH₃ OH/CH₂ Cl₂ (with 0.3-1.0% NH₄ OH)]provided 81 mg (49%) of the title Compound 250e (colorless solid).

mp 187°-192° C. (dec.); [α]_(D) =-22° (c 0.32, CH₃ OH)

Mass Spec: 731 (M+H)⁺

Elemental Analysis: Calcd for C₄₀ H₅₄ N₆ O₇.0.32 H₂ O: C, 65.21; H,7.48; N, 11.41. Found: C, 65.31; H, 7.53; N, 11.31.

EXAMPLE 251 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-bis(hydroxymethyl)ethyl 1,1-dimethylethyl ester (Compound251d)

(a) Compound 251a ##STR512##

Compound 251a was prepared by the method described in Curran et al.,Synthetic Comm. 20, 3575 (1990).

(b) Compound 251b ##STR513##

To a slurry of (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one)(3.8 g, 8.96 mmol) in 10 mL of dry CH₂ Cl₂ was added t-BuOH (0.929 mL,9.856 mmol). The mixture was cooled to 0° C. and a solution of Compound251a (1.434 g, 4.48 mmol) in 5 mL of CH₂ Cl₂ was added. The reactionmixture was warmed to RT and stirred for 2 h after which time themixture was diluted with 75 mL of EtOAc and 90 mL of 1:1:1 sat. NaHCO₃-10% Na₂ SO₃ -brine was added. The mixture was stirred vigorously for 1h, the two phases separated and the organic phase washed with brine,dried (MgSO₄) and concentrated. The crude residue was purified by flashchromatography on silica, eluting with a stepwise gradient of hexane to50% EtOAc-hexane to obtain Compound 251b (0.775 g, 54%) as a colorlessoil.

(c) Compound 251c ##STR514##

To 1.95 mL (2.681 mmol) of a 1.4M MeLi solution in Et₂ O was added 5 mLof THF. The solution was cooled to -78° C. and a solution of Compound251b (0.775 g, 2.437 mmol) in 5 mL of THF was slowly added. Anadditional 1 mL of MeLi solution was added twice at intervals of 1 h andthe mixture slowly warmed to -40° C. After 1 additional h, the reactionwas quenched by adding 0.4 mL of HOAc in 5 mL of THF, warmed to RT anddiluted with H₂ O. The mixture was extracted with EtOAc and the extractswashed with sat. NaHCO₃ and brine, dried (MgSO₄) and concentrated. Thecrude residue was purified by flash chromatography on silica gel elutingwith a stepwise gradient of hexane to 75% EtOAc-hexane to affordCompound 251c (0.475 g, 58%) as a colorless oil.

(d) Compound 251d ##STR515##

Compounds 161a and 251c were reacted by a five-step procedure analogousto that used for the conversion of Compound 161c to Compound 162 (Et₃ Nwas used in the coupling of the p-nitrophenyl carbonate of Compound 251cwith Compound 161a) to give the title Compound 251d (off-white solid).High Res. Mass Spec. (M+H)⁺ =576.3285 (Δ_(ppm) =2.2).

EXAMPLE 252 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 2-fluoro-1,1-dimethylethyl 1,1-dimethylethyl ester (Compound 252d)

(a) Compound 252a ##STR516##

Compound 48 and 2-methyl-1-fluoro-2-propanol (Bergmann et al., J. Chem.Soc., 2259 (1958)) were converted to Compound 252a by a two-stepprocedure analogous to that used for the conversion of Compound 149c to149e.

(b) Compound 252b ##STR517##

Compound 252a was converted to Compound 252b by a procedure analogous tothat of Example 140a.

(c) Compound 252c ##STR518##

Compound 252b was converted to Compound 252c by a procedure analogous tothat of Example 21.

(d) Compound 252d ##STR519##

Compound 252c was converted to the title Compound 252d (white solid) bya procedure analogous to that of Example 140e except that the reactionwas run at RT for 18 h and at reflux for 2 h.

m.p. 174°-176° C.; [α]_(D) =-6.0° (c=0.2, CH₃ OH)

Analysis calculated for:C₃₀ H₄₄ N₃ O₆ F C, 64.15; H, 7.90; N, 7.48; F,3.38. Found: C, 63.99; H, 7.96; N, 7.81; F, 3.35.

EXAMPLE 253 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-dimethylethyl(4-phenyl-1H-imidazol-2-yl)methyl ester (Compound253e)

(a) Compound 253a ##STR520##

4-Phenylimidazole (2.5 g, 17.3 mmol) was stirred with trityl chloride(4.8 g, 17.2 mmol) in acetone (37 ml) and Et₃ N (2.9 ml, 20.8 mmol) for3 h. The mixture was concentrated, dissolved in CH₂ Cl₂ and washed withH₂ O, brine, dried (Na₂ SO₄) and concentrated. The product crystallizedand was dried in vacuo to yield Compound 253a (6.49 g, 97%, mp 185°-188°C.).

(b) Compound 253b ##STR521##

Compound 253a (2.0 g, 5.17 mmol) in 50 ml of dry THF was cooled to -45°C. and tert-butyl lithium (1.7M in hexanes, 6.1 ml, 10.34 mmol) wasadded dropwise and the reaction was stirred for 30 min. DMF (1.9 ml,25.85 mmol) was added and the reaction was stirred for 1.5 h at whichpoint saturated aq. NH₄ Cl was added and product was extracted withEtOAc. The EtOAc solution was washed with H₂ O, brine, dried (Na₂ SO₄),and concentrated in vacuo to yield crystalline Compound 253b (2.09 g,94%, mp 185°-188° C.).

(c) Compound 253c ##STR522##

Compound 253b (2.09 g, 5.0 mmol) was dissolved in THF:EtOH:CHCl₃ (15ml:15 ml:20 ml), cooled to 0° C. and NaBH₄ (0.33 g, 8.57 mmol) was addedportionwise. After 1 h, the reaction mixture was diluted with CH₂ Cl₂and washed with H₂ O, brine, dried (Na₂ SO₄) and concentrated. Theproduct crystallized from Et₂ O to yield Compound 253c (1.8 g, 86%, mp183°-190° C.).

(d) Compound 253d ##STR523##

Compounds 253c and 48 were reacted by a three-step procedure analogousto that used for the conversion of Compound 149c to 150 (Et₃ N and DMFwere used in the reaction of the p-nitrophenyl carbonate of Compound253c with Compound 48) to give Compound 253d.

(e) Compound 253e ##STR524##

Compound 253d was dissolved in EtOH (4.7 mL) and HOAc (19 mL) and thereaction mixture was stirred at 40° C. for 2 h, concentrated in vacuoand the residue triturated with Et₂ O. The resulting solid waschromatographed through 80 g of silica gel eluting with CHCl₃ :MeOH:NH₄OH (89:10:1) to afford the title Compound 253e (0.12 g, 54%) as a whitesolid.

m.p. 109°-115° C.; [α]_(D) =-5.6° (c=0.85, MeOH).

Analysis Calc. for C₃₆ H₄₅ N₅ O₆.1.13 H₂ O: C, 65.11;H, 7.17; N, 10.55Found: C, 65.12;H, 6.99; N, 10.54

EXAMPLE 254 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(3,4 -dihydroxy-1-oxobutyl)-L-valinamide (Compound 254f)

(a) Compound 254a ##STR525##

To a 0° C. solution of diazomethane/Et₂ O (see Compound 1a(i) forpreparation) was added dropwise 3-butenoic acid (4.94 mL, 58.0 mmol)over 5 min. The solution was swirled until colorless, then washed withaqueous NaHCO₃ and dried (Na₂ SO₄). The Et₂ O was distilled off to giveCompound 254a (4.32 g, 74%).

(b) Compound 254b ##STR526##

To a solution of Compound 254a (4.25 g, 42.4 mmol) andN-methylmorpholine N-oxide (8.07 mL of a 60% solution by weight in H₂ O)in acetone (30 mL) and H₂ O (20 mL) was added OsO₄ (70.0 mg, 0.275 mmol)and the resulting solution stirred at RT for 18 h. A solution of NaHSO₃(0.50 g in 5 mL H₂ O) was then added, the resulting black solutionstirred at RT for 30 min, then filtered through Celite (acetone wash).The volatiles were removed and the residual aqueous solution wassaturated with NaCl and extracted with EtOAc. The combined organicextracts were dried (Na₂ SO₄), concentrated and purified on silica gel(150 mL) using a gradient from 1:1 hexane:EtOAc to 100% EtOAc to giveCompound 254b (3.15 g, 55%) as a slightly yellow oil.

(c) Compound 254c ##STR527##

To a solution of Compound 254b (1.00 g, 7.46 mmol) in acetone (10 mL)and 2,2-dimethoxypropane (10 mL) was added p-toluenesulfonic acidhydrate (7 mg, 0.037 mmol) and the solution was stirred at RT for 18 h.Saturated aqueous NaHCO₃ solution was added and the mixture wasconcentrated in vacuo. The residue was partitioned between H₂ O andEtOAc and the combined organic extracts were washed with H₂ O, dried(Na₂ S0₄), and concentrated in vacuo. The oil was purified on silica gel(150 mL) using 10:1 hexane:EtOAc to give Compound 254c (1,260 g, 97%) asa colorless oil.

(d) Compound 254d ##STR528##

Compound 254c was converted to Compound 254d by a procedure analogous tothat of Example 70c (THF used as solvent).

(e) Compound 254e ##STR529##

Compounds 254d and 61 were reacted by a two step procedure analogous tothat used for the conversion of Compound 48 to Compound 52 to giveCompound 254e (white foam).

(f) Compound 254f ##STR530##

Compound 254e was converted to the title Compound 254f (white solid;mixture of diastereomers at *) by a procedure analogous to that ofExample 202c.

m.p.=156°-160° C.; [α]_(D) =-11.1° (c=0.28; MeOH)

High resolution Mass Spec. (FAB): Calculated (M+H)⁺ (for C₃₄ H₅₃ N₄O₈)=645.3861;

Observed (M+H)⁺ =645.3862 Δ=0.2 ppm

EXAMPLE 255 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,4-Dihydroxy-1-oxo-butyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 255b)

(a) Compound 255a ##STR531##

Compounds 254d and 48 were reacted by a two-step procedure analogous tothat used for the conversion of Compound 48 to 52 to give Compound 255a(white solid).

(b) Compound 255b ##STR532##

Compound 255a was converted to the title Compound 255b (white solid;mixture of diastereomers) by a procedure analogous to that of Example202c.

m.p.=145°-150° C.; [α]_(D) =+5.0° (c=0.20; MeOH)

Mass Spec. (FAB): (M+H)⁺ =546;

Elemental Analysis: (for C₂₉ H₄₃ N₃ O₇.1.19 H₂ O) Calculated: C, 61.42;H, 8.07; N, 7.41 Found: C, 61.20; H, 7.83; N, 7.63

EXAMPLE 256 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, 1,1-dimethylethyl-3-pyridinylmethyl ester (Compound 256)##STR533##

3-Pyridine carbinol and Compound 48 were converted to the title Compound256 (colorless solid) by a three-step procedure analogous to that usedfor the conversion of Compound 149c to 150 (DMF was used in the couplingof the p-nitrophenyl carbonate of 3-pyridine carbinol to Compound 48).

m.p. 167°-170° C.; [α]_(D) =-16° (c 0.24, CH₃ OH)

Mass Spec. 579 (M+H)⁺

Analysis Calc. for C₃₂ H₄₂ N₄ O₆.0.37 H₂ O: C, 65.66; H, 7.36;N, 9.57Found: C, 65.65; H, 7.39;N, 9.58

EXAMPLE 257 Preparation of[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]-carbonyl]propyl]carbamicacid, (2-benzoxazolyl)methyl ester (Compound 257c)

(a) Compound 257a ##STR534##

To a solution of 350 mg (2.35 mmol) of Compound 171a in 5 mL of CH₂ Cl₂and 2.5 mL of pyridine at 0° C. was added 475 mg (2.35 mmol) ofp-nitrophenylchloroformate in 2.5 mL of CH₂ Cl₂. The mixture was stirredat 0° C. for 2 h. The mixture was diluted with EtOAc and washed with 1MNaOH, H₂ O, and brine. The organic layer was dried (Na₂ SO₄), filtered,and concentrated in vacuo. Flash chromatography of the residue (20-40%EtOAc-hexane) afforded 567 mg (77%) of Compound 257a.

(b) Compound 257b ##STR535##

To neat tert-L-leucine (146 mg, 1.11 mmol) was added aqueous 1N NaOH(1.1 mL). After stirring for several minutes, a dioxane (3 mL) solutionof Compound 257a (140 mg, 2.61 mmol) was added, followed by Et₃ N (0.23mL, 1.65 mmol) . The reaction mixture was stirred for 26 h, diluted withH₂ O, and brought to pH 4 with 5% KHSO₄. The aqueous solution wasextracted with EtOAc, the aqueous layer brought back to pH 3 with more5% KHSO₄ and extracted with EtOAc. The combined organic layers weredried (Na₂ SO₄) and evaporated in vacuo to an oil. The residue waspurified by flash chromatography (silica gel, 3 by 15 cm), eluting withEtOAc: CH₂ Cl₂ (1:1), then 10%MeOH: CH₂ Cl₂ to give Compound 257b (227.7mg, 67% yield) as a colorless oily solid.

(c) Compound 257c ##STR536##

To a solution of Compound 257b (152 mg, 0.50 mmol) in DMF (2.5 mL) at 0°C. under argon was added HOBT (105 mg, 0.78 mmol), and then EDCI (95 mg,0.50 mmol). After 45 min, solid Compound 54 (226 mg, 0.51 mmol) wasadded and the mixture was brought to RT. After stirring 24 h, thereaction mixture was partitioned between EtOAc and saturated NaHCO₃. Thecombined organics were dried (Na₂ SO₄) and evaporated in vacuo to givean oily solid which was purified by flash chromatography (silica gel, 3by 15 cm), eluting with MeOH:NH₄ OH:CH₂ Cl₂ (5:0.5:94.5, 6:0.6:93.4, andthen 7:0.7:92.3) to give the title Compound 257c (151 mg, 42% yield) asa colorless solid. m.p. 149°-159° C.; [α]_(D) ²⁵ =-18.2° (c 0.28, MeOH).

Mass Spec.: (FAB): 732 (M+H).

Anal. Calc. for C₄₀ H₅₃ N₅ O₈ C, 65.64; H, 7.30; N, 9.57 Found: C,65.79; H, 7.54; N, 9.66

EXAMPLE 258 Preparation of [R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamic acid,1,1-dimethylethyl-1-(3-pyridinyl)ethyl ester (Compound 258b)

(a) Compound 258a ##STR537##

To a solution of 536 mg (5.00 mmol) of 3-pyridinecarboxaldehyde in 16.5mL of dry THF at -78° C. was added 3.4 mL (5.5 mmol) of methyllithium(1.6M in Et₂ O) (internal temperature<-55° C.). The resulting yellowsolution was warmed to 0° C. and quenched by the addition of 30 mL ofsaturated NH₄ Cl. The reaction mixture was extracted with Et₂ O and theorganic layer dried (Na₂ SO₄), filtered, and concentrated in vacuo toprovide 458 mg of Compound 258a. The aqueous layer was saturated withNaCl and extracted with Et₂ O. Concentration in vacuo provided anadditional 74 mg (total 532 mg) of product.

(b) Compound 258b ##STR538##

Compounds 258a and 48 were converted to the title Compound 258b(colorless solid) by a three-step procedure analogous to that used forthe conversion of Compound 149c to 150 (DMF was used in the coupling ofthe p-nitrophenyl carbonate of Compound 258a to Compound 48).

m.p. 161°-170° C.; [α]_(D) =-14° (c 0.21, CH₃ OH)

Mass Spec. 593 (M+H)⁺

Anal. Calc. for C₃₃ H₄₄ N₄ O₈ C, 66.87; H, 7.48; N, 9.45 Found: C,66.54; H, 7.64; N, 9.28

EXAMPLE 259 Preparation of [1R*, 2S* (2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(hyroxyacetyl)-L-valinamide (Compound 259) ##STR539##

Compound 61 and glycolic acid were reacted by a two-step procedureanalogous to that used for the conversion of Compound 48 to Compound 52to afford the title Compound 259 (white solid).

m.p. 208°-210° C.

Mass Spec. High resolution 601.3595, error 1.0 ppm, theory 601.3601

Analysis Calc. for C₃₂ H₄₈ O₇ N₄.1.34 H₂ O: C, 61.50; H, 8.17; N, 8.97Found: C, 61.77; H, 8.15; N, 8.70

EXAMPLE 260 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[3-(1H-indol-3-yl)-1-oxo-propyl]-L-valinamide (Compound 260) ##STR540##

Compound 61 and 3-indolpropionic acid were reacted by a two-stepprocedure analogous to that used for the conversion of Compound 48 toCompound 52 to afford the title Compound 260 (white solid).

m.p. 212°-214° C.; [α]_(D) =-38.1° (c=0.2, CH₃ OH)

Analysis for:C₄₁ H₅₅ N₅ O₈.0.65 H₂ O Calculated:C, 67.86; H, 7.82; N,9.65. Found: C, 67.95; H, 7.77; N, 9.56.

EXAMPLE 261 Preparation of[1S-[1R*,2S*[2S*,3R*(R*)]]]-[3-[[3-[(2-Hydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 261c)

(a) Compound 261a ##STR541##

A solution of t-butyl magnesium chloride (2M in Et₂ O, 21.55 mL, 43.1mmol) was added to a stirred solution of ethyl pyruvate (5 g, 43.1 mmol)in THF (75 mL) at -78° C. The reaction mixture was stirred at -78° C.for 15 min, RT for 1 h, diluted with EtOAc, and washed with 1N HClfollowed by sat. NaHCO₃. The organic layer was dried (MgSO₄),concentrated, and the resulting oil was fractionally distilled undervacuum affording 3.5 g (47%) of Compound 261a as a colorless oil (b.p.45°-50° C. at 1.2 mm).

(b) Compound 261b ##STR542##

A 0.5M aq. solution of LiOH (10.64 mL) was added to a solution ofCompound 261a (1.0 g, 5.75 mmol), stirred at 75° C. for 8 h,concentrated in vacuo, and the residue concentrated from toluene. Theresidue was triturated from Et₂ O to afford 0.9 g (ca. 100% ) o fCompound 261b.

(c) Compound 261c ##STR543##

To a solution of Compound 261b (0.114 g, 0.75 mmol), HOBT monohydrate(0.135 g, 0.88 mmol) in 2 mL dry DMF at 0° C. was added N-methylmorpholine (0.1634 mL, 1.49 mmol), EDCI hydrochloride (0.1434 g, 0.75mmol) and the resulting mixture was stirred at 0° C. for 15 min. Themixture was treated with Compound 54 (0.3 g, 0.68 mmol) and stirred atRT for 20 h, concentrated, and the residue partitioned between EtOAc andsat. NaHCO₃. The organic layer was dried (MgSO₄), concentrated, and thecrude product was subjected to flash chromatography (silica gel/CH₂ Cl₂-MeOH-NH₄ OH 95:5:0.5) affording 0.193 mg (50%) of a mixture of the twodiastereomeric products. This mixture was subjected to prep. HPLC(Waters Prep Nova-Pack HR C18, 6 micron, 30×300 mm; eluent:MeOH-water-TFA 30:70:0.05 to 90:10:0.05; UV 254 nm). The fractions fromthe slower moving isomer were made basic with sat. NaHCO₃, concentrated,and the residue partitioned between EtOAc/1:1 brine-sat. NaHCO₃. Theorganic phase was dried (MgSO₄), concentrated, the resulting white solidwas triturated from 10:1 hexane-Et₂ O to afford 19 mg (5%) of the titleCompound 261c as a white solid.

m.p. 97°-100° C.; [α]_(D) =-5.2° (c=0.91, MeOH).

High resolution Mass Spec.: (M+H)⁺ =572.3688, theoretical: (M+H)⁺=572.3699 (Δ 1.9 ppm error).

Similar work-up of the fractions from the faster moving peak afforded 23mg (6%) of Compound 262f.

EXAMPLE 262 Preparation of [1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-Hydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 262f)

(a) Compound 262a ##STR544##

A 70% solution of t-butyl hydroperoxide in water (340.5 ml, 2.38 mol)was extracted with 300 ml CH₂ Cl₂. The organic layer was added to astirred mixture of SeO₂ (3.67 g, 33.1 mmol) and benzoic acid (8.1 g,66.2 mmol) in 50 ml CH₂ Cl₂. The mixture was cooled to 0° C. and2,3,3-trimethylbutene (65 g, 0.662 mol) was added and the mixturestirred at RT for 14 h. The mixture was washed with 5% aq. KOH, brineand dried (MgSO₄). The volatiles were removed by distillation and theresidue was cooled to ca. 0° C. 100 ml HOAc was added followed by 100 mlMe₂ S added dropwise over 15 min. The reaction was stirred at RT for 3h, cooled to 0° C. and made basic with 20% aq. K₂ CO₃. The mixture wasextracted with Et₂ O and the organic extracts washed with sat. NaHCO₃,dried (MgSO₄), and the solvent removed by distillation at atmosphericpressure followed by distillation of the product (90°-100° C., 25 mm) toafford 20 g (26.5%) of Compound 262a.

(b) Compound 262b ##STR545##

Diethyl D-tartrate (618 mg, 3 mmol) and Ti(iPrO)₄ (0.744 ml, 2.5 mmol)were added to a stirred suspension of 4 Å activated powdered molecularsieves in 175 ml dry CH₂ Cl₂ at 0° C. The mixture was cooled to -20° C.and a 5.5M solution of t-butyl hydroperoxide in 2,2,4-trimethylpentane(18.2 ml, 100 mmol) was added. After 20 min, a solution of Compound 262a(5.7 g, 50 mmol) in 25 ml CH₂ Cl₂ was added and the mixture stirred at-20° C. for 14 h. After warming to 0° C., 15 ml H₂ O was added, themixture stirred at RT for 30 min, 30% aq. NaOH saturated with NaCl (3ml) was added and the reaction stirred at RT for 25 min. The aqueouslayer was extracted with CH₂ Cl₂, the combined extracts dried (MgSO₄)and concentrated by distillation at atmospheric pressure followed bydistillation of Compound 262b (105°-107° C., 25 mm; 4.75 g, 73%).

(c) Compound 262c ##STR546##

A solution of Compound 262b (2.3 g, 17.7 mmol) in 10 ml Et₂ O was addedto a suspension of LiAlH₄ (1.477 g, 38.9 mmol) in 100 ml Et₂ O at -5° C.and stirred at RT for 30 min. The mixture was cooled to 0° C., andquenched with 10% aq. H₂ SO₄ saturated with Na₂ SO₄. The aqueous layerwas extracted with EtOAc and the combined extracts washed with sat.NaHCO₃ and brine and dried (MgSO₄). Concentration in vacuo followed byrecrystallization from hexane gave 1.5 g (64%) of Compound 262c as awhite solid.

(d) Compound 262d ##STR547##

A solution of DMSO (2.578 ml, 36.3 mmol) in 3 ml CH₂ Cl₂ was addeddropwise at -78° C. to a stirred solution of oxalyl chloride (1.585 ml,18.2 mmol) over 5 min. and stirred at -78° C. for 10 min. A solution ofCompound 262c (2.18 g, 16.5 mmol) in 25 ml CH₂ Cl₂, was added dropwiseand stirred for 15 min. at -78° C. Et₃ N (11.51 ml, 82.6 mmol) was addedand the reaction allowed to come to RT. The mixture was diluted withadditional CH₂ Cl₂, washed with 10% H₂ SO₄, the combined aqueous phaseextracted with CH₂ Cl₂, and the combined organic layer washed with sat.NaHCO₃, dried (MgSO₄), and concentrated by distillation at atmosphericpressure to afford 2.15 g (100%) of Compound 262d as a pale gummy solid.

(e) Compound 262e ##STR548##

NaClO₂ (1.81 g, 20 mmol) and sulfamic acid (1.94 g, 20 mmol) were addedin succession to a stirred solution of Compound 262d (2.0 g, 15.4 mmol)in 30 ml 1:1 THF-water at 0° C. The mixture was allowed to warm to RT,stirred for 30 min., diluted with CH₂ Cl₂ and ca. 1 ml Me₂ S was addedfollowed by a small quantity of H₂ O. The organic layer was separated,the aqueous layer was extracted with CH₂ Cl₂, the combined organic layerwas dried (MgSO₄) and concentrated to afford a yellow gummy solid whichwas recrystallized from hexanes to afford 1.45 g (64.5%) of Compound262e as a pale solid.

(f) Compound 262f ##STR549##

N-methylmorpholine (0.037 ml, 0.34 mmol) and BOP-reagent (150 mg, 0.34mmol) were added at RT in succession to a stirred mixture of Compound262e (45 mg, 0.31 mmol) and Compound 54 (137 mg, 0.31 mmol) in 0.5 mldry DMF. The mixture was stirred at RT for 60 h, concentrated in vacuo,the residue partitioned between EtOAc and sat. NaHCO₃, and the organiclayer dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby flash chromatography (1"×12" silica gel/CH₂ Cl₂ to CH₂ Cl₂ :MeOH:aq.NH₄ OH 99:1:0.1 stepwise to 92.5:7.5:0.75) to afford 120 mg (68%) of thetitle Compound 262f as a white solid.

m.p. 204°-205° C.

Anal. Calcd. for C₃₂ H₄₉ N₃ O₆.1.22 H₂ O: C, 64.73; H, 8.73; N, 7.08Found: C, 64.73; H, 8.42; N, 7.10.

EXAMPLE 263 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(methylamino)carbonyl]-3-methyl-L-valinamide (Compound 263d)

(a) Comoound 263a ##STR550##

Compounds 88a and 48 were reacted by a procedure analogous to that ofExample 51 to give Compound 263a (white foam).

(b) Compound 263b ##STR551##

Compound 263a was converted to Compound 263b (white foam) by a procedureanalogous to that of Example 61.

(c) Compound 263c ##STR552##

Compound 263b and methyl isocyanate were reacted by a procedureanalogous to that of Example 46 to give Compound 263c (colorless oil).

(d) Compound 263d ##STR553##

Compound 263c was converted to the title Compound 263d (white solid) bya procedure analogous to that of Example 21.

m.p.=174°-178° C.; [α]_(D) =-15.0 ° (c=0.28; MeOH)

High resolution Mass Spec. (FAB): Calcualted (M+H)⁺ (for C₃₃ H₅₂ O₆N₅)=614.3917;

Observed (M+H)⁺ =614.3936 Δ=3.1 ppm.

EXAMPLE 264 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-homoserinamide (Compound 264d)

(a) Compound 264a ##STR554##

To a solution of L-homo-serine (596 mg, 5.0 mmol) and NaHCO₃ (420 mg,5.0 mmol) in 14 ml of H₂ O-acetone (1:1) was addedN-benzyloxycarbonyloxy succinimide (1.25 g, 5.0 mmol). The mixture wasstirred overnight at RT. Acetone was removed under reduced pressure. Theaqueous solution was washed with CH₂ Cl₂ and then acidified to pH 2.5with 6N HCl solution and extracted with EtOAc. The combined extractswere washed with H₂ O and brine and dried (Na₂ SO₄). Concentration invacuo afforded 980 mg (77%) of Compound 264a.

(b) Compound 264b ##STR555##

To a stirred solution of Compound 264a (506 mg, 2.0 mmol) in 10 ml ofdry DMF was added tert-butyldimethylsilyl chloride (1.81 g, 12.0 mmol),followed by imidazole (1.63 g, 24.0 mmol). The mixture was stirred for24 h at RT. CH₃ OH (35 ml) was added and the mixture was stirred foranother 14 h. The solvent was removed under reduced pressure and theresidue was dissolved in EtOAc. The organic layer was washed with 10%citric acid and brine and dried over Na₂ SO₄. Concentration in vacuofollowed by flash chromatography (CHCl₃ -EtOAc-HOAc: 60:40:1) afforded638 mg (87%) of Compound 264b as a colorless oil.

(c) Compound 264c ##STR556##

Compounds 54 and 264b were reacted by a procedure analogous to that ofExample 93f to give Compound 264c.

(d) Compound 264d ##STR557##

Compound 264c was converted to the title Compound 264d (white solid) bya procedure analogous to that of Example 162.

m.p. 168°-170° C.; [α]_(D) =-25.6° (C 0.36, MeOH).

Mass Spec. (FAB): 679⁺ (M+H)⁺.

Analysis Calc. for C₃₇ H₅₀ N₄ O₈.0.20H₂ O: C, 65.12; H, 7.44; N, 8.21.Found: C, 65.04; H, 7.48; N, 8.29.

EXAMPLE 265 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[[(4-phenyl-1H-imidazol-2-yl)methoxy]carbonyl]-L-valinamide (Compound265b)

(a) Compound 265a ##STR558##

Compounds 253c and 61 were reacted by a three-step procedure analogousto that used for the conversion of Compound 149c to 150 (Et₃ N and DMFwere used in the reaction of the p-nitrophenyl carbonate of Compound253c with Compound 61) to give Compound 265a.

(b) Compound 265b ##STR559##

Compound 265a was converted to Compound 265b (white solid) by aprocedure analogous to that of Example 253e.

m.p. 140°-145° C.; [α]_(D) =-1.8° (MeOH, c=0.5)

Analysis Calc. for C₄₁ H₅₄ N₆ O₇.1.61H₂ O: C, 63.80; H, 7.47; N, 10.89.Found: C, 63.75; H, 7.39; N, 10.94.

EXAMPLE 266 Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(3,3-Dimethyl-5-oxo-2-pyrrolidinyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydrxmy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 266c)

(a) Compound 266a ##STR560##

Compound 266a was prepared by the method of Yamazaki et al., Chem.Pharm. Bull., 24, 3011 (1976).

(b) Compound 266b ##STR561##

Compound 266a was converted to Compound 266b by a procedure analogous tothat of Example 70c (except THF:H₂ O:DME (2:1:0.5) was used).

(c) Compound 266c ##STR562##

Compounds 266b and 54 were reacted by a procedure analogous to that ofExample 93f to give the title Compound 266c along with its diastereomerCompound 267 (1:1). Compound 266c (white lyophilate) was isolated byflash chromatography (CHCl₃ -MeOH-NH₄ OH 95:5:0.5 to 90:10:1) on silicagel followed by preparative HPLC (CH₃ CN-H₂ O-TFA 62:38:0.1)purification (YMC SH ODS-365-10, S-10 column).

¹ H-NMR (400 MHz, CD₃ OD): δ 7.10-7.30 (m, 10H), 4.27 (m, 1H), 3.70 (s,1H), 3.58-3.75 (m, 3H), 3.14 (m, 2H), 2.50-2.84 (m, 6H), 2.26 (d,J=16.7, 1H), 1.93 (d, J=16.7, 1H), 1.29 (s, 9H), 0.79 (s, 3H), 0.76 (s,3H).

High resolution Mass Spec. Calc. for C₃₂ H₄₇ N₄ O₆ : 583.3496; Found:583.3506, Δ=1.7 ppm.

EXAMPLE 267 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(3,3-Dimethyl-5-oxo-2-pyrrolidinyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 267) ##STR563##

Compound 267, the diastereomer of Compound 266c, was isolated bypreparative HPLC as described in Example 266c.

¹ H-NMR (400 MHz, CD₃ OD):δ 7.10-7.30 (m, 10H), 4.16 (m, 1H), 3.63 (s,1H), 3.56-3.73 (m, 3H), 3.10 (m, 2H), 2.63-2.80 (m, 5H), 2.58 (m, 1H),2.47 (d, J=16.7, 1H), 2.38 (d, J=16.7, 1H), 1.29 (s, 9H), 0.97 (s, 3H),0.93 (s, 3H).

High resolution Mass Spec. Calc. for C₃₂ H₄₇ N₄ O₆ : 583.3496; Found:583.3505, Δ=1.7 ppm.

EXAMPLE 268 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamicacid, (1H-imidazol-2-yl)-methyl 1,1-dimethylethyl ester (Compound 268b)

(a) Compound 268a ##STR564##

Compounds 249a and 48 were reacted by a three-step procedure analogousto that used for the conversion of Compound 149c to 150 (Et₃ N and DMFwere used in the reaction of the p-nitrophenyl carbonate of Compound249a with Compound 48) to give Compound 268a.

(b) Compound 268b ##STR565##

Compound 268a was converted to Compound 268b (white solid) by aprocedure analogous to that of Example 253e.

m.p. 143°14 147° C. (dec.); [α]_(D) =-5°-9° (c=0.16, MeOH).

Analysis Calcd. for C₃₀ H₄₁ N₅ O₆.0.45 H₂ O (575.79): C, 62.58; H, 7.34;N, 12.16. Found: C, 62.57; H, 7.35; N, 12.08. Mass Spec. (FAB): (M+H)⁺=568⁺

EXAMPLE 269 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(2,2-Dimethyl-1-oxo-propyl)amino]-2-hydroxyl-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 269) ##STR566##

Compound 54 and trimethylacetic acid were converted to the titleCompound 269 (white solid) by a procedure analogous to that of Example262f except that a mixture of DMF and CH₂ Cl₂ was used and noN-methylmorpholine was added.

m.p. 100°-104° C. ("softening" at 84°-99° C.); [α]_(D) =+10.1° (c=0.8.5, MeOH).

High resolution Mass Spec. 528.3 428⁺ for C₃₀ H₄₆ O₅ N₃ (calc.528.3437⁺) Δ=1.7 ppm.

EXAMPLE 270 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2-Formyl-2,3-dihydro-1-isoindol-1-yl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1.1-dimethylethyl ester (Compound 270g)

(a) Compound 270a ##STR567##

A solution of benzoyl peroxide (97%; 0.043 g), N-bromosuccinimide (11.74g, 0.066 mol) and o-tolylacetic acid (10.0 g, 0.066 mol) in CCl₄ (600ml) was heated at 90° C. for 3.5 h. Upon cooling, the reaction wasfiltered to remove a yellow precipitate, and the filtrate wasconcentrated in vacuo to a yellow solid. This solid was recrystallizedfrom CCl₄ to afford 9.20 g (64%) of Compound 270a as a white crystallinesolid.

(b) Compound 270b ##STR568##

After heating a solution of Compound 270a (9.0 g, 0.04 mol) in SOCl₂(9.0 ml) at 50° C. for 3 h, the excess reagent was removed at reducedpressure, and the resulting yellow oil heated to 80° C. under a 250 wattlamp. Br₂ (2.5 ml) was added and the reaction continued at 80° C. for 4h before cooling and removing the excess reagent under reduced pressure.The resulting brown residue was stirred in MeOH for 30 min at RT thenconcentrated in vacuo to an orange oil which was chromatographed on asilica gel column, eluting the column with toluene to afford 8.0 g (65%)of Compound 270b as a yellow oil.

(c) Compound 270c ##STR569##

Benzylamine (2.04 ml, 18.69 mmol) was added to a stirred solution ofCompound 270b (2.0 g, 6.23 mmol) in toluene (13 ml) at 0° C. Thereaction was warmed to RT where it remained for 72 h before filteringoff a yellow precipitate under Ar. The solid was washed thoroughly withtoluene and the filtrate diluted with a solution of anhydrous Et₂ Osaturated with HCl gas. The mother liquor was decanted and the remainingyellow gum dried under high vacuum to afford 1.35 g (50%) of Compound270c as a green foam.

(d) Compound 270d ##STR570##

Compound 270c was converted to Compound 270d by a procedure analogous tothat of Example 2.

(e) Compound 270e ##STR571##

Compound 270d was converted to Compound 270e by a procedure analogous tothat of Example 129 (except 1.1 eq. of N-methylmorpholine was also addedto the reaction mixture).

(f) Compound 270f ##STR572##

A solution of aqueous NaOH (0.736 ml, 1N) was added at RT to a rapidlystirred solution of Compound 270e in THF (lml). After 20 min, thesolution was concentrated in vacuo then dried under high vacuum toafford 0.136 g (51%) of Compound 270f as a brown/green solid.

(g) Compound 270g ##STR573##

Compounds 270f and 54 were reacted by procedure analogous to that ofExample 55 (DMF only used) to give the title Compound 270 g as a mixtureofdiastereomers.

m.p. 174°-176° C.; [α]_(D) =-30° (c 0.1, MeOH)

Mass spec: HRMS C₃₅ H₄₅ O₆ N₄ : 617.3328+: calculated 617.3339+, Δ=1.8ppm.

EXAMPLE 271 Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-1-(phenylmethyl)-3-[[2-hydroxy-4-phenyl-3-[(3,3,3-trifluoro-2-hydroxy-1-oxopropyl)amino]butyl]amino]propyl]carbamicacid, 1,1-dimethylethyl ester (isomer A) (Compound 271) ##STR574##

To a solution of trifluorolactic acid (0.107 g, 0.75 mmol, prepared asdescribed in Burstein, Can. J. Chem., 39, 1848 (1961)), HOBT monohydrate(0.135 g, 0.88 mmol) in 2.1 mL dry DMF at RT was added in successionN-methylmorpholine (0.163 mL, 1.49 mmol), Compound 54 (0.3 g, 0.68 mmol)and EDCI hydrochloride (0.143 g, 0.75 mmol). The resulting mixture wasstirred at RT for 16 h, concentrated, and the residue partitionedbetween EtOAc and sat. NaHCO₃. The organic layer was dried (MgSO₄),concentrated, and the crude product was purified by flash chromatography(silica gel/CH₂ Cl₂ to CH₂ Cl₂ -MeOH-NH₄ OH 90:10:1, stepwise gradient)affording 0.21 g (54%) of a mixture of the two diastereomeric products.This mixture was subjected to preparative HPLC (Waters Prep Nova-Pack HRC18, 6 micron, 30×300 mm; eluent: MeOH-water-TFA 20:80:0.05 to90:10:0.05; UV 254 nm). The desired fractions containing the fastereluting component on C18 were made basic with sat. NaHCO₃, concentrated,and the residue partitioned between EtOAc/brine. The organic phase wasdried (MgSO₄), concentrated, and the resulting solid was triturated from5:1 pentane-Et₂ O to afford 51 mg (13%) of the title Compound 271 as awhite solid.

m.p. 160°-163° C.; [α]_(D) =+2.25° (c=0.2, MeOH).

High resolution Mass Spec.: (M+H)⁺ =570.2809, theoretical: (M+H)⁺=570.2791 (Δ 3.1 ppm error).

EXAMPLE 272 Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-1-(phenylmethyl)-9-[[2-hydroxy-4-phenyl-3-[(3,3,3-trifluoro-2-hydroxy-1-oxopropyl)amino]butyl]amino]propyl]carbamicacid, 1,1-dimethylethyl ester (isomer B) (Compound 272) ##STR575##

Compound 272 (white solid), the diastereomer of Compound 271, wasisolated by preparative HPLC (work up of the fraction from the slowermoving peak) as described in Example 271.

m.p. 127°-130° C.; [α]_(D) =+5.0° (c=0.3, MeOH).

High resolution mass spectrum: (M+H)⁺ =570.2786, theoretical: (M+H)⁺=570.2791 (Δ 0.9 ppm error).

EXAMPLE 273 Preparation of [1R*,2S*(2S*,3R*)]-N²-[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide(Compound 273b)

(a) Compound 273a ##STR576##

2-Aminomethylbenzimidazole and Compound 245b were reacted by a procedureanalogous to that of Example 245c to give Compound 273a.

(b) Compound 273b ##STR577##

Compounds 273a and 54 were reacted by a two-step procedure analogous tothat used for the conversion of Compound 70b to Compound 70d (DMF only;no N-methylmorpholine was added) to give the title Compound 273b (whitesolid) along with its valine diastereomer Compound 274. Thediastereomers were separated on a 30 ml silica column eluting with 2-8%MeOH/CH₂ Cl₂ which was increased in 0.5% units with 0.1% NH₄ OH. TLC(SiO₂)R_(f) =0.40 (CH₂ Cl₂ :MeOH: NH₄ OH 90:10:1)

m.p. 182°-186° C. (dec); [α]_(D) =-22° (c=0.25, MeOH)

Analysis Calcd. for: C₃₉ H₅₃ N₇ O₆ ·2.5 H₂ O C, 61.57 H, 7.68 N, 12.89Found: C, 61.23 H, 7.33 N, 12.78.

EXAMPLE 274 Preparation of [1S*,2R*(2R*,3S*)]-N₂-[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-D-valinamide(Compound 274) ##STR578##

Compound 274 (white solid) was isolated as the slower moving isomer bythe procedure described in Example 273b.

TLC(SiO₂)R_(f) =0.35 (CH₂ Cl₂ :MeOH:NH₄ OH 90:10:1)

m.p. 186°-189° C. (dec); [α]_(D) =-10.5° (c=0.25, MeOH)

Analysis Calcd. for: C₃₉ H₅₃ N₇ O₆ ·2.4 H₂ O C, 61.77 H, 7.67 N, 12.93Found: C, 61.54 H, 7.28 N, 13.03

EXAMPLE 275 Preparation of [1S-(1R*,2S*),(S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl 2-hydroxy-1,1-dimethylpropyl ester (Compound275h)

(a) Compound 275a ##STR579##

Compound 275a was prepared from (R)-methyl lactate by a procedureanalogous to that of Example 232a.

(b) Compound 275b ##STR580##

Compound 275a was converted to Compound 275b by a two-step procedureanalogous to that used for the conversion of Compound 149b to Compound149d.

(c) Compound 275c ##STR581##

Compound 16b was reacted with benzylchloroformate by a procedureanalogous to that used in Example 122 (reaction run at 0° C. for 2 h) togive Compound 275c.

(d) Compound 275d ##STR582##

Solid Compound 275c (1.21 g; 2.91 mmol) was added to a saturatedsolution of HCl gas in 45 ml of EtOAc at 0° C. The reaction wasstoppered and stirred for 3 h at 0° C. The solution was purged with N₂for 15 min and the volatiles were removed in vacuo to afford 1.03 g(˜100%; contained trace solvent) of Compound 275d as a white solid.

(e) Compound 275e ##STR583##

Compounds 275b and 275d were reacted by a procedure analogous to that ofExample 161e to give Compound 275e.

(f) Comoound 275f ##STR584##

Compound 275e was converted to Compound 275f by a procedure analogous tothat of Example 61.

(g) Compound 275q ##STR585##

Compounds 1b(i) and 275f were reacted by a procedure analogous to thatof Example 4b to give Compound 275g.

(h) Compound 275h ##STR586##

Compound 275g was converted to the title Compound 275h (white solid) bya procedure analogous to that of Example 162.

m.p. 77°-87° C. (dec.); [α]D⁼⁻⁸.5 ° (c 0.27, MeOH).

Mass Spec. FAB: M+H=574 (M+H)

Analysis calc. for C₃₁ H₄₇ N₃ O₇ ·0.64 H₂ O: C, 63.62; H, 8.31; N, 7.18;Found: C, 63.57; H, 8.33; N, 7.23.

EXAMPLE 276 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-6-[4-[2-(4-morpholinyl)-2-oxoethoxy]phenyl]-5-hexenyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethl ester (Compound 276d)

(a) Compound 276a ##STR587##

Compound 235e was converted to Compound 276a by a procedure analogous tothat of Example 18.

(b) Compound 276b ##STR588##

Compound 276a and 4-(2-bromoacetyl)-morpholine (J. Med. Chem., 35, 1685(1992)) were converted to Compound 276b by a two-step procedureanalogous to that used for the conversion of Compound 20 to Compound173.

(c) Compound 276c ##STR589##

Compound 276b was converted to Compound 276c by a two-step procedureanalogous to that of Example 177.

(d) Compound 276d ##STR590##

Compound 276c was converted to the title Compound 276d (white solid) bya procedure analogous to that of Example 21.

m.p. 115°-116° C.; [α]Hg (365)=-27.1° (c 0.14, MeOH ).

Mass Spec. (FAB): 713⁺ (M+H)⁺.

Analysis Calcd. for C₃₈ H₅₆ N₄ O₉ : C, 64.00; H, 7.92; N, 7.86. Found:C, 63.78; H, 7.93; N, 8.08.

EXAMPLE 277 Preparation of [R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanedyl)]biscarbamicacid, 1,1-dimethylethyl-2-hydroxy-1-(3-pyridinyl)ethyl ester (Compound277e)

(a) Compound 277a ##STR591##

To a 0° C. solution of vinyl magnesium bromide (41.0 mL of a 1.0Msolution in THF) was added dropwise over 1 h a solution of pyridine3-carboxaldehyde (4.00 g, 37.3 mmol) in THF (50 mL). The resultingorange-yellow solution was allowed to warm to RT and stirred for 24 hunder argon. The reaction mixture was cooled to 0° C., then was quenchedby slow addition of aqueous NH₄ Cl (55 mL of a 1M solution). EtOAc wasadded and the resulting emulsion was filtered through Celite in asintered glass funnel under vacuum. The aqueous layer was extracted withEtOAc and the combined organic extracts were dried (Na₂ SO₄) andconcentrated in vacuo to give a red oil which was purified on silica gel(500 mL) using a stepwise gradient from 1:1 to 1:5 hexanes:ethyl acetateas eluent to give Compound 277a (3.89 g; 77%) as a pale yellow oil.

(b) Compound 277b ##STR592##

Ozone was bubbled through a solution of 1.00 g (7.40 mmol) of Compound277a in 25 mL of CH₃ OH at -78° C. for 20 min. After purging with N₂ andwarming to 0° C., the reaction mixture was diluted with 3 mL of H₂ O andNaBH₄ (420 mg, 11.1 mmol) was added. The mixture was stirred for 30 minat 0° C. and for 1 h at RT then quenched by the addition of 10 mL ofsaturated NH₄ Cl. The pH was adjusted to 4 with 20 mL of 1M HCl, and thereaction mixture was concentrated in vacuo. Flash chromatography onsilica gel [2% CH₃ OH/CH₂ Cl₂, then 3-10% CH₃ OH/CH₂ Cl₂ (with 1.0% NH₄OH)]provided 717 mg (70%) of Compound 277b.

(c) Compound 277c ##STR593##

To a solution of 677 mg (4.86 mmol) of Compound 277b in 20 mL of dry CH₂Cl₂ at 0° C. were added 0.75 mL (5.4 mmol) of Et₃ N, 30 mg DMAP, and 769mg (5.10 mmol) of t-butyldimethylsilylchloride. The reaction mixture waswarmed to RT over 4 h and then stirred for 4 days. The reaction mixturewas diluted with 75 mL of EtOAc, and washed with saturated NaHCO₃ andbrine. The organic layer was dried (Na₂ SO₄), filtered, and concentratedin vacuo to provide, after flash chromatography on silica gel (25-100%EtOAc-hexane), 1.12 g (91%) of Compound 277c.

(d) Compound 277d ##STR594##

Compounds 277c and 54 were reacted by a two-step procedure analogous tothat used for the conversion of Compound 147b to Compound 147d to giveCompound 277d.

(e) Compound 277e ##STR595##

Compound 277d was converted to the title Compound 277e (white solid) bya procedure analogous to that of Example 162.

m.p. 75°-85° C.; [α]_(D) =-13° (c 0.28, CH₃ OH)

Mass Spec. 609 (M+H)⁺

Analysis Calcd. for C₃₃ H₄₄ N₄ O₇ ·1.03 H₂ O: C, 63.18; H, 7.40; N,8.93. Found: C, 63.28; H, 7.28; N, 8.83.

EXAMPLE 278 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[(2-hydroxy-2-methyl-1-oxopropyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 278) ##STR596##

Compound 54 and 2-hydroxyisobutyric acid were reacted by a procedureanalogous to that of Example 269 to give the title Compound 278 (whitesolid). m.p. 162°-166° C. ("softening" at 156°-161° C.); [α]_(Hg)365=-2.9° (c=0.99, CH₃ OH).

Mass Spec. (FAB), 530 (M+H⁺)

Analysis Calcd. for C₂₉ H₄₃ N₃ O₆ ·0.48 H₂ O: C, 64.70; H, 8.23; N,7.81. Found: C, 64.72; H, 8.32; N, 7.79.

EXAMPLE 279 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-(hydroxymethyl)-2-methyl-1-oxopropyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 279) ##STR597##

Compound 54 and 2,2-dimethyl-3-hydroxypropionic acid were reacted by aprocedure analogous to that of Example 269 (CH₂ Cl₂ only used) to givethe title Compound 279 (white solid).

m.p. 73°-76° C. ("softening" at 66°-72° C.); [α]_(D) =+3.6°; (c=0.76,CH₃ OH).

Mass Spec. (FAB), 544 (M+H⁺)

Analysis Calcd. for C₃₀ H₄₅ N₃ O₆ ·0.29 H₂ O: C, 65.64; H, 8.37; N,7.65. Found: C, 65.64; H, 8.33; N, 7.81.

EXAMPLE 280 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[[(1H-inden-2-yl)methoxy]carbonyl]-L-valinamide (Compound 280b)

(a) Compound 280a ##STR598##

A solution of 2-carboethoxyindene (1.0 g, 6.24 mmol; see Treibs, Chem.Ber., 93, 545 (1960)) in 15 ml of dry toluene was treated with 4 eq. ofa 1M solution of diisobutylaluminum hydride in toluene (24.96 ml) at RT.After 4 h at RT, the reaction was cooled in an ice-bath and MeOH wasadded. The mixture was filtered and the solvents evaporated yielding thecrude product as a colorless oil which was purified by chromatography onsilica column eluting with 60% EtOAc/hexane to afford 593 mg (77%) ofCompound 280a as a colorless solid.

(b) Compound 280b ##STR599##

L-Valine and Compounds 280a and 54 were reacted by a three-stepprocedure analogous to that described for the conversion of Compound171a to Compound 257c to give the title Compound 280b (colorless solid).

m.p. 148°-154° C. (dec); [α]_(D) =-18.5° (c 0.22, MeOH)

Mass Spec. (FAB) :715⁺ (M+H)⁺

Analysis Calcd. for: C₄₁ H₅₄ N₄ O₇ +0.75 H₂ O: C, 67.61; H, 7.68; N,7.69 Found: C, 67.62; H, 7.52; N, 7.68.

EXAMPLE 281 Preparation of[1R*,2S*(2S*,3R*)]]-N-[3-[[1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]-N²-[(2-quinolinylmethoxy)carbonyl]-L-valinamide (Compound 281c)

(a) Compound 281a ##STR600##

A solution of 7.25 mL (7.25 mmol; 1.0M in Et₂ O) of LiAlH₄ was dilutedwith 4 mL of dry Et₂ O and cooled to -60° C. To this was added, over 30min, a solution of 1.15 g of methyl quinaldate in 7 mL of dry Et₂ O. Themixture was warmed to -25° C., stirred for 15 min, and treated with 10mL of Et₂ O which was saturated with H₂ O. The mixture was warmed to 0°C. and quenched by the addition of a solution of 360 mg of NaOH in 2 mLof H₂ O. The mixture was diluted with 100 mL of Et₂ O and washed with H₂O and brine. The organic layer was dried (Na₂ SO₄), filtered, andconcentrated in vacuo to give crude material which was purified by flashchromatography on silica gel (25-100% EtOAc-hexane) to afford 445 mg(46%) of Compound 281a.

(b) Compound 281b ##STR601##

Compound 281a and L-valine were reacted by a two-step procedureanalogous to that described for the conversion of Compounds 70a(i) and70a(ii) to Compound 70c to give Compound 281b.

(c) Compound 281C ##STR602##

Compounds 281b and 54 were reacted by a procedure analogous to that ofExample 55 (DMF only used) to give the title Compound 281c (whitesolid).

m.p. 177°-190° C. (dec.); [α]_(D) =-12° (C 0.33, CH₃ OH)

Mass Spec. 728 (M=H)⁺

Analysis Calcd. for: C₄₁ H₅₃ N₅ O₇ ·0.85 H₂ O: C, 66.25; H, 7.42; N,9.42 Found: C, 66.10; H, 7.28; N, 9.57

EXAMPLE 282 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[[4-[2-(2-pyridinyl)ethoxy]phenyl]methyl]propyl]carbamicacid, 2-hydroxy-1,1-dimethylethyl ester (Compound 282g)

(a) Compound 282a ##STR603##

To a suspension of Compound 175c (400 mg, 1.43 mmol) in THF (1.5 mL) wasadded PPh₃ (0.564 g, 2.15 mmol), followed by 2-(2-hydroxyethyl)pyridine(256.5 mg, 2.15 mmol) and DEAD (0.374 g, 2.15 mmol). The resultingsolution was stirred at RT for 18 h. The reaction mixture wasconcentrated in vacuo and purified by silica gel chromatography, elutingwith EtOAc (10% to 100%)-hexane to afford Compound 282a (0.254 g, 45%yield).

(b) Compound 282b ##STR604##

To a solution of Compound 282a (200 mg, 0.52 mmol) in MeOH (ca. 8 mL)was added NaN₃ (101.45 mg, 1.56 mmol) and NH₄ Cl (50 mg, 0.93 mmol) andthe mixture heated at reflux for 18 h. The solution was cooled to RT,and the solvent removed under vacuum. The residue was taken in EtOAc andwashed with H₂ O and brine. The combined organic phase was dried(MgSO₄), and concentrated in vacuo to yield Compound 282b (187 mg, 71%)as a gummy white residue.

(c) Compound 282c ##STR605##

Compound 282b (180 mg, 0.421 mmol) in 4M HCl in dioxane (3.36 mL) wasstirred at RT for 1 h, and concentrated in vacuo to yield a yellowresidue which was azeotroped from CHCl₃ and then toluene to yieldCompound 282c as a foamy yellow solid (197 mg, ca. 100% yield, crude).

(d) Compound 282d ##STR606##

To Compound 282c (195 mg, 0.595 mmol) in DMF (0.5 mL) was added i-Pr₂NEt (0.72 mL, 4.16 mmol), followed by a solution of the Compound 161d(242 mg, 0.655 mmol) in DMF (ca. 0.5 mL) and the mixture stirred at RTfor 18 h. The reaction mixture was concentrated in vacuo and the residuetaken in EtOAc and washed with 1:1 saturated NaHCO₃ :brine. The combinedorganic layer was dried (MgSO₄), filtered and concentrated in vacuo toyield a yellow gummy residue which was purified by flash chromatography,eluting with CH₃ OH (1% to 30%)-CH₂ Cl₂ to afford Compound 282d (250 mg,75% yield) as a yellow solid.

(e) Compound 282e ##STR607##

To a solution of Compound 282d (235 mg, 0.421 mmol) in THF (2.5 mL) wasadded H₂ O (12 μL), followed by triphenylph0sphine (122 mg, 0.463 mmol)and the mixture stirred at RT for 18 h. The reaction mixture wasconcentrated in vacuo, and purified on silica gel, eluting with CH₂ Cl₂:CH₃ OH:aq. NH₄ OH (99:1:0.02 to 85:15:0.1) to afford Compound 282e (145mg, 65% yield) as a gummy white solid.

(f) Compound 282f ##STR608##

To a solution of Compound 282e (134 mg, 0.252 mmol) in DMF (0.5 mL ) wasadded the Compound 1b(i) (66.36 mg, 0.252 mmol) and the mixture heatedat 110° C. for 6 h, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with CH₂ Cl₂ :CH₃ OH:aq.NH₄ OH (99:1:0.02 to 90:10:1) to afford Compound 282f (114 mg, 57%yield) as a white residue.

TLC(SiO₂) R_(f) =0.22 (9:1:0.1 CH₂ Cl₂ :MeOH:aq. NH₄ OH - Rydon)

(g) Compound 282g ##STR609##

Compound 282f (114 mg, 0.143 mmol) in a mixture of HOAc:THF:H₂ O (3:1:1,1.5 mL) was stirred at RT for 40 h, and then heated at 50° C. for 4 h.The reaction mixture was concentrated in vacuo and the residue purifiedby silica gel chromatography, eluting with CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH(97.5:2.5:0.025 to 90:10:1) to afford the title Compound 282 g (50 mg,51% yield) as a foamy white solid.

m.p. 106°-108° C.; [α]_(D) =-4.0° (c=0.2, CH₃ OH).

Analysis for: C₃₇ H₅₂ N₄ O₈ ·0.84 H₂ O Calculated: C, 63.85; H, 7.77; N,8.05. Found: C, 63.86; H, 7.58; N, 8.04.

EXAMPLE 283 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[[4-(2-methoxyethoxy)phenyl]methyl]propyl]carbamicacid, 2-hydroxy-1,1-dimethylethyl ester (Compound 283) ##STR610##

Compound 175c and 2-methoxyethanol were converted to the title Compound283 (white solid) by a seven-step procedure analogous to that used inExample 282.

m.p. 118°-120° C.; [α]_(D) =-3.90° (c=0.2, CH₃ OH).

Analysis for: C₃₃ H₅₁ N₃ O₉ ·0.38 H₂ O Calculated: C, 61.87; H, 8.14; N,6.56. Found: C, 61.88; H, 8.0.8; N, 6.55.

EXAMPLE 284 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(N-formyl-L-alanyl)-3-methyl-L-valinamide (Compound 284d)

(a) Compound 284a ##STR611##

Compound 263b and N-carbobenzyloxy-L-alanine were reacted by a procedureanalogous to that of Example 51 to give Compound 284a.

(b) Compound 284b ##STR612##

Compound 284a was converted to Compound 284b by a procedure analogous tothat of Example 61 (EtOH was used instead of MeOH).

(c) Compound 284c ##STR613##

Compound 284b was reacted with formic acetic anhydride by a procedureanalogous to that of Example 129 to give Compound 284c.

(d) Compound 284d ##STR614##

Compound 284c was converted to the title Compound 284d (white solid) bya procedure analogous to that of Example 21.

m.p. 167°-170° C., [α]_(D) =-25.7° (MeOH, C=0.6).

Mass Spec. 656 (M+H)⁺

EXAMPLE 285 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(N-formyl-L-phenylalanyl)-3-methyl-L-valinamide (Compound 285)##STR615##

Compound 263b and N-carbobenzyloxy-L-phenylalanine were converted to thetitle Compound 285 (white solid) by a four-step procedure analogous tothat described in Example 284.

m.p. 117°-119° C., [α]_(D) =-9.6° (MeOH, c 1.12).

Mass Spec. 732 (M+H)⁺

EXAMPLE 286 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(N-formylglycyl)-3-methyl-L -valinamide (Compound 286b)

(a) Compound 286a ##STR616##

Compound 263b and N-formylglycine were reacted by a procedure analogousto that of Example 51 to give Compound 286a.

(b) Compound 286b ##STR617##

Compound 286a was converted to the title Compound 286b (white solid) bya procedure analogous to that of Example 21.

m.p. 180°-183° C.

EXAMPLE 287 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[3,3-Dimethyl-2-[[(methylamino)carbonyl]oxy]-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamicacid, 1,1-dimethylethyl ester (Compound 287d)

(a) Compound 287a ##STR618##

Vinyl magnesium bromide was added to pivaldehyde by a procedureanalogous to that of Example 277a to give Compound 287a as ayellow-orange oil.

(b) Compound 287b ##STR619##

To a 0° C. suspension of THF-washed Nail (0.116 g of an 80% oildispersion) in anhydrous THF (5 mL) was added dropwise a solution ofCompound 287a (0.400 g; 3.50 mmol) in THF (10 mL). The reaction mixturewas allowed to warm to RT and stirred for 1 h. After recooling to 0° C.,a solution of methyl isocyanate (0.25 mL; 4.20 mmol) in THF (1.5 mL) wasadded dropwise. The reaction was allowed to warm to RT and stirred for 4h. Aqueous NH₄ Cl (10 mL of a 1M solution) and EtOAc (20 mL) were added.The aqueous layer was saturated with NaCl and extracted with EtOAc. Thecombined organic extracts were dried (Na₂ SO₄) and concentrated in vacuoto give Compound 287b (0.302 g; 50%) as a yellow oil.

(c) Compound 287c ##STR620##

Compound 287b was converted to Compound 287c by a procedure analogous tothat of Example 238b.

(d) Compound 287d ##STR621##

Compound 287c was converted to the title Compound 287d (white solid) bya procedure analogous to that of Example 93f.

m.p.=85°-89° C. (softens at 65°-70° C.); [α]_(D) =-5.8° (c 0.12, MeOH)

Mass Spec. (M+H)⁺ =615

Analysis Calculated for C₃₃ H₅₀ N₄ O₇.0.80 H₂ O: C, 63.00; H, 8.27; N,8.91 Found: C, 63.00; H, 8.20; N, 8.63

EXAMPLE 288 Preparation of [1R*,2S*(2S*,3R*)]-N²-[[(2Benzoxazolyl)methoxy]carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[(4-hydroxyphenyl)methyl]propyl]-L-valinamide(Compound 288f)

(a) Compound 288a ##STR622##

Compound 175b was converted to Compound 288a by a two-step procedureanalogous to that described for the conversion of Compound 282a toCompound 282c.

(b) Compound 288b ##STR623##

Compound 288a was converted to Compound 288b by a procedure analogous tothat of Example 122 except that benzylchloroformate was used.

(c) Compound 288c ##STR624##

Compounds 288b and 1b(i) were converted to Compound 288c by a two-stepprocedure analogous to that used for the conversion of Compound 282d toCompound 282f (except that the second step was performed in i-PrOH at80° C.).

(d) Compound 288d ##STR625##

Hydrogenation (balloon) of 120 mg (0.175 mmole) of Compound 288c in 10ml of MeOH over 30 mg of 10% Pd/C catalyst afforded 80 mg (0.174 mmole,100%) of Compound 288d as a solid foam.

(e) Compound 288e ##STR626##

Compound 288e was prepared as described in Example 171.

(f) Compound 288f ##STR627##

Compounds 288d and 288e were reacted by a procedure analogous to that ofExample 93f to give the title Compound 288f (white solid).

m.p. 175°-177° C.; [α]_(D) =-20.1 (c. 0.92, MeOH)

Mass Spec.: (M+H)⁺ 734⁺

Analysis Calc. for C₃₉ H₅₁ N₅ O₉ ·0.33 H₂ O: C, 63.32; H, 7.04; N, 9.47.Found: C, 63.32; H, 7.03, N, 9.27.

EXAMPLE 289 Preparation of[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3.1-propanediyl)]biscarbamicacid, (1H-benzimidazol-2-yl)methyl 1,1-dimethylethyl ester (Compound289e)

(a) Compound 289a ##STR628##

Compounds 93c and 48 were reacted by a procedure analogous to that ofExample 149e (DMF used) to give Compound 289a.

(b) Compound 289b ##STR629##

Compound 289a was converted to Compound 289b by a procedure analogous tothat of Example 140a.

(c) Comoound 289c ##STR630##

Compound 289b was converted to Compound 289c by a procedure analogous tothat of Example 21.

(d) Compound 289d ##STR631##

Compound 289c was converted to Compound 289d by a procedure analogous tothat of Example 140e.

(e) Compound 289e ##STR632##

Compound 289d was converted to the title Compound 289e (white solid) bya procedure analogous to that of Example 7 (1 eq. of hydrazinemonohydrate was added).

m.p. 95°-105° C.; [α]_(D) =-9.3° (c=0.2, CH₃ OH).

Mass Spec. (FAB) (M+H)⁺ =618

Analysis calc. for C₃₄ H₄₃ N₅ O₆ ·1.02H₂ O: C, 64.19; H, 7.14; N, 11.01;Found: C, 64.39; H, 6.89; N, 10.81.

EXAMPLE 290 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-(1H-imidazol-1-yl)-ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 290d)

(a) Compound 290a ##STR633##

A mixture of imidazole (2 g; 29 mmol), ethyl bromoacetate (3.2 ml; 29mmol) and K₂ CO₃ (8.1 g; 58 mmol) in 30 ml of DMF was heated to 65° C.for 18 h. After cooling to RT, the reaction mixture was filtered througha glass-fritted funnel and the filtrate was concentrated in vacuo. Theresidue was purified on a 5×15 cm silica gel column, using 5% MeOH/CH₂Cl₂ as the mobile phase to afford 2.10 g (49%) of Compound 290a as alight orange oil.

(b) Compound 290b ##STR634##

Compound 290a was converted to Compound 290b by a procedure analogous tothat of Example 281a.

(c) Compound 290c ##STR635##

Compounds 290b and 175c were reacted by a procedure analogous to that ofExample 282a to give Compound 290c.

(d) Compound 290d ##STR636##

Compounds 290c and 16b were reacted by a procedure analogous to that ofExample 226b to give the title Compound 290d (white solid).

m.p. 130°-135° C. (dec); [α]₃₆₅ =-14.1° (0.33, MeOH).

Mass Spec. CI: (M+H) 654

Analysis calc. for C₃₅ H₅₁ N₅ O₇ ·0.52 H₂ O; C, 63.38; H, 7.91; N,10.56; Found: C, 63,31; H, 7,97; N, 10.63.

EXAMPLE 291 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[(4-hydroxy-2,2-dimethyl-1-oxobutyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 291d)

(a) Compound 291a ##STR637##

Compound 291a was prepared as described in U.S. Pat. No. 4,732,902.

(b) Compound 291b ##STR638##

To a solution of Compound 291a (2.0 g, 11.76 mmol) in DMF was addedt-butyldimethylsilyl chloride (10.635 g, 70.56 mmol) and imidazole(8.006 g, 117.6 mmol). The resulting mixture was stirred at RT for 24 h.MeOH (100 mL) was added and the reaction mixture was stirred at RT for24 h. The mixture was diluted with EtOAc and washed with 10% citric acid(until aqueous phase had pH=2) followed by H₂ O and brine. The organicphase was separated, dried (MgSO₄) and concentrated. The crude residuewas purified by flash chromatography on silica gel eluting with 90:9:1followed by 80:19:1 hexane-EtOAc-HOAc to afford Compound 291b (1.8 g,62%) as a colorless oil.

(c) Compound 291c ##STR639##

Compounds 291b and 54 were reacted by a procedure analogous to that ofExample 55 to give Compound 291c.

(d) Compound 291d ##STR640##

Compound 291c was converted to Compound 291d (white solid) by aprocedure analogous to that of Example 162.

m.p. 70°-74° C. (softening at 60°-65° C.); [α]_(D) =-1.2° (c=1.0, CH₃OH).

Mass Spec. (FAB) (M+H)⁺ =558

Analysis calc. for C₃₁ H₄₇ N₃ O₆ ·0.35H₂ O: Calculated C, 66.01; H,8.52; N, 7.45; Found: C, 65.91; H, 8.55; N, 7.55.

EXAMPLE 292 Preparation of[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamic acid,(2-benzothiazolyl)methyl ester (Compound 292b)

(a) Compound 292a ##STR641##

2-Aminothiophenol and glycolic acid were reacted by a procedureanalogous to that of Example 171a to give Compound 292a.

(b) Compound 292b ##STR642##

Compound 292a and L-tert-leucine were reacted by a three-step procedureanalogous to that used for the conversion of Compound 171a to Compound257c to give the title Compound 292b (colorless solid).

m.p. 148°-154° C. (dec); [α]_(D) =-14.5° (c=0.25, MeOH).

Mass Spec. (FAB): (M+H)⁺ =748⁺

Analysis Calcd. for C₄₀ H₅₃ N₅ SO₇ ·1.78 H₂ O: C, 61.60; H, 7.31; N,8.98; S, 4.11 Found: C, 61.62; H, 6.96; N, 8.96; S, 4.01

EXAMPLE 293 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[2-hydroxy-1-oxo-2-(trifluoromethyl)propyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethylester (isomer A) (Compound 293b)

(a) Compound 293a ##STR643##

1,1,1-Trifluoroacetone cyanohydrin (5 g, 39.4 mmol) was added to 5 mLconc. H₂ SO₄ with stirring at RT. The mixture was heated at 120° C. for15 min and 20 mL ice cold water was added. After refluxing for 15 h, thereaction was cooled to RT, saturated with Na₂ SO₄ and extracted with Et₂O. The combined Et₂ O extracts were dried (MgSO₄), the Et₂ O distilledoff with a vigruex column at atmospheric pressure and the residuesublimed (0.5 mm at 150°-200° C.) to afford 4.3 g (69%) of the Compound293a as a white solid.

(b) Compound 293b ##STR644##

To a solution of Compound 293a (117.5 mg, 0.75 mmol) and HOBTmonohydrate (0.135 g, 0.88 mmol) in 2 mL dry DMF at RT was added insuccession Compound 54 (0.3 g, 0.68 mmol), N-methylmorpholine (0.1634mL, 1.49 mmol), and EDCI hydrochloride (0.1434 g, 0.75 mmol). Theresulting mixture was stirred at RT for 14 h, concentrated, and theresidue partitioned between EtOAc and sat. NaHCO₃. The organic layer wasdried over MgSO₄, concentrated, and the crude product was purified byflash chromatography (silica gel/CH₂ Cl₂ to CH₂ Cl₂ -MeOH-NH₄ OH90:10:1, continuous gradient) affording 0.3 g (76%) of a mixture of thetwo diastereomeric products (at *). This mixture was subjected to prep.HPLC (Waters Prep Nova-Pack HR C18, 6 micron, 40×300 mm; eluent:MeOH-water-TFA 50:50:0.05 to 100:0:0.05; UV 254 nm). The desiredfractions containing the faster eluting component were made basic withsat. NaHCO₃, concentrated, and the residue partitioned between EtOAc/1:1brine-sat. NaHCO₃. The organic phase was dried (MgSO₄) and concentratedto afford 100 mg (25%) of the title Compound 293b (single diastereomer)as a white solid.

m.p. 203°-204° C.; [α]_(D) =+1.5° (c=1.2, MeOH).

Mass Spec. 584 (M+H)⁺.

Analysis calcd. for C₂₉ H₄₀ N₃ O₆ F₃.0.55H₂ O: C, 58.69; H, 6.98; N,7.08; F, 9.60. Found: C, 58.55; H, 6.81; N, 7.22; F, 10.04.

EXAMPLE 294 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[2-hydroxy-1-oxo-2-(trifluoromethyl)propyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethylester (isomer B) (Compound 294) ##STR645##

Preparative HPLC separation as described in Example 293b and work up ofthe fraction from the slower moving peak afforded 95 mg (24%) of thetitle Compound 294 (single diastereomer) as a white solid.

m.p. 92°-95° C.; [α]_(D) =-2.5° (c 0.75, MeOH).

Mass Spec. 584 (M+H)⁺.

Analysis calcd. for C₂₉ H₄₀ N₃ O₆ F₃.1.23H₂ O: C, 57.50; H, 7.06; N,6.94; F, 9.41. Found: C, 57.70; H, 6.70; N, 6.74; F, 9.67.

EXAMPLE 295 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-(hydroxyimino)-3,3-dimethyl-1-oxobutyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl]propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 295) ##STR646##

A solution of Compound 213c (60 mg, 91% pure, 0.10 mmol) , hydroxylaminehydrochloride (22.5 mg, 0.324 mmol) and 3 drops of pyridine in 1.0 mlabsolute EtOH was stirred at RT for 2 h. The reaction mixture wasconcentrated in vacuo to provide an oily residue which was purified bychromatography on a silica gel column (11 mm×20 cm) eluting with CH₂ Cl₂-MeOH-aq. NH₄ OH in a gradient from 98-1.8-0.2 to 92-7.2-0.8 to provide36 mg (63% yield) of Compound 295 (white solid) as a single isomer(oxime geometry not determined).

m.p. 100°-104° C. ("softening" at 87°-100° C.); [α]_(D) =-12.4°; (c=1.1,CH₃ OH)

Mass Spec. (FAB): 571 (M+H⁺)

Analysis calc. for C₃₁ H₄₆ N₄ O₆ ·0.87H₂ O: C, 63.49; H, 8.21; N, 9.55Found: C, 63.47; H, 8.02; N, 9.57

EXAMPLE 296 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-(methoxyimino)-3,3-dimethyl-1-oxobutyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 296) ##STR647##

Compound 213c was reacted with methoxyamine hydrochloride by a procedureanalogous to that of Example 295 to give the title Compound 296 (whitesolid).

m.p. 199°-201° C. ("softening" at 175°-198° C.); [α]_(D) =-13.5°;(c=0.38, CH₃ OH)

Mass Spec. (FAB): 585 (M+H⁺)

EXAMPLE 297 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[[4-[2-(2-pyridinyl)ethoxy]phenyl]methyl]propyl]-N²-(2-methoxycarbonyl)-3-methyl-L-valinamide (Compound 297g)

(a) Compound 297a ##STR648##

A solution of Compound 282c (410 mg, 1.25 mmol) in CH₂ Cl₂ (40 mL) andCH₃ OH (5 mL) was stirred with K₂ CO₃ (3 g) at RT for 1 h, filtered, andthe filtrate concentrated in vacuo to yield the free amine (390 mg, ca.95% yield) as a gummy yellow residue. This material was coupled toCompound 88a (350 mg, 1.31 mmol) in 2 mL DMF, along with 251 mg (1.31mmol) EDCI, 177 mg (1.31 mmol) HOBT and 170 μl (1.55 mmol)N-methylmorpholine, using a procedure analogous to that described inExample 93f, to give Compound 297a (421 mg, 61%).

(b) Compound 297b ##STR649##

Compound 297a (420 mg, 0.729 mmol) was treated with triphenylphosphine(210.5 mg, 0.802 mmol) in THF (4.5 mL) and water (20 μL), using aprocedure analogous to that of Example 282e to afford Compound 297b (318mg, 79%) as a gummy residue.

(c) Compound 297c ##STR650##

Compound 297b (314 mg, 0.571 mmol) was taken in DMF (1.0 mL) and heatedwith the Compound 1b(i) (150.2 mg, 0.571 mmol) using a procedureanalogous to that of Example 282f to afford Compound 297c (296 mg, 63%yield) as a yellow residue.

TLC(SiO₂) R_(f) =0.28 (9:1:0.1 CH₂ Cl₂ :CH₃ OH: aq. NH₄ OH-Rydon)

(d) Compound 297d ##STR651##

To a solution of Compound 297c (291 mg, 0.358 mmol) in DMF (1 mL), wasadded i-Pr₂ NEt (130 μL, 0.752 mmol) and2-trimethylsilylethylchloroformate (72 mg, 0.394 mmol) at 0° C., and themixture stirred for 2.5 h. The reaction mixture was diluted with EtOAcand poured into a 1:1 mixture of saturated NaHCO₃ :H₂ O. The organiclayer was washed with brine, dried (MgSO₄) and concentrated under vacuumto yield a gummy residue which was purified by silica gelchromatography, eluting with CH₃ OH (3% to 8%)-CH₂ Cl₂ to affordCompound 297d (305 mg, 89% yield) as a foamy white residue.

TLC(SiO₂) R_(f) =0.53 (8% CH₃ OH-CH₂ Cl₂ -Rydon)

(e) Compound 297e ##STR652##

Compound 297d (303 mg, 0.316 mmol) in EtOH (4 mL) was treated with 20%Pd(OH)₂ /C (104 mg) under a H₂ atmosphere for 18 h. The catalyst wasfiltered and the filtrate concentrated. The crude product was purifiedby silica gel chromatography, eluting with CH₃ OH (2.5% to 7.5%)-CH₂Cl₂, to afford Compound 297e (185 mg, 71% yield) as a yellow solid.

TLC(SiO₂) R_(f) =0.27 (8% CH₃ OH-CH₂ Cl₂ -Rydon)

(f) Compound 297f ##STR653##

To a solution of Compound 297e (85 mg, 0.103 mmol) in p-dioxane (0.8 mL)was added a 1:1 mixture of saturated NaHCO₃ :H₂ O (400 uL), followed bymethyl chloroformate (0.114 mmol, 8.7 uL) and the mixture stirred at RTfor 30 min. Additional methyl chloroformate was added (3.3 eq.; 27 μltotal in small portions), and stirred at RT for a total of 3.5 h. Thereaction mixture was diluted with EtOAc and washed with saturated NaHCO₃and brine and the organic layer was dried and concentrated in vacuo toyield crude Compound 297f (86 mg, 94% yield) as as gray solid. TLC(SiO₂)R_(f) =0.25 (5% CH₃ OH/CH₂ Cl₂ -PMA)

(g) Compound 297g ##STR654##

To a solution of Compound 297f (86 mg, 0.097 mmol) in dry THF (1 mL) wasadded n-Bu₄ NF (76.6 mg, 0.293 mmol) and the reaction mixture heated at45° C. for 4 h. The mixture was concentrated in vacuo andchromatographed on silica gel, eluting with CH₃ OH (2.5% to 6.5%)-CH₂Cl₂ with aq. NH₄ OH (0.25% to 0.6%) to afford the title Compound 297g(44 mg, 62%) as a white solid

m.p. 127°-130° C.; [α]_(D) =-16° (c=0.2, CH₃ OH).

Analysis Calc. for C₄₀ H₅₇ N₅ O₈ ·0.52 H₂ O Calculated: C, 64.46; H,7.85; N, 9.40 Found: C, 64.31; H, 7.49; N, 9.55

EXAMPLE 298 Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[2Hydroxy-3-[[2-hydroxy-3-[[(2-hydroxy-1,1-dimethylethoxy)carbonyl]amino]-4-phenylbutyl]amino]-1-[[4-[2-(2-pyridinyl)ethoxy]phenyl]methyl]propyl]carbamic acid,1,1-dimethylethyl ester (Compound 298e)

(a) Compound 298a ##STR655##

To a solution of 1.4 g (4.6 mmol) of Compound 142a in 10 ml of dioxanewas added 10 ml of 4N HCl in dioxane and stirred at RT for 4 hr. Removalof solvent afforded 1.24 g (≦100%) of Compound 298a as a white foam.

(b) Compound 298b ##STR656##

A solution of 381 mg (1.57 mmol) of Compound 298a, 579 mg (1.57 mmol) ofCompound 161d, and 1.48 ml (8.65 mmol) of i-pR₂ NEt in 10 ml of dry DMFwas stirred at RT for 5 days. After removal of solvent the residue wastaken into EtOAc and washed with 1N HCl and brine. The oil residueobtained after drying (MgSO₄) and removal of solvent was purified byflash chromatography on silica gel (10% EtOAc-hexane) to afford 589 mg(86%) of Compound 298b as a white solid.

(c) Compound 298c ##STR657##

A solution of 550 mg (1.26 mmol) of Compound 298b was hydrogenated(balloon) over 55 mg 10% Pd/C catalyst in 10 ml of MeOH at RT for 2 hr.After filtration of catalyst through Celite, removal of solvent gave 423mg (82%) of Compound 298c as a white foam.

(d) Compound 298d ##STR658##

A solution of 184 mg (0.45 mmol) of Compound 298c and 165 mg (0.43 mmol)of Compound 282a in 1 ml of dry DMF was heated at 100° C. for 7 h. Afterremoval of solvent, the residue was purified by flash chromatography ona 35 cc column of silica gel. Elution with CHCl₃ :MeOH:NH₄ OH (95:5:0.5)afforded 113 mg (33%) of Compound 298d as a solid foam.

TLC(SiO₂) R_(f) =0.32 CHCl₃ :MeOH:NH₄ OH 90:10:1)

(e) Compound 298e ##STR659##

A solution of 110 mg (0.14 mmol) of Compound 298d in 1 ml HOAc:H₂ O:THF(3:1:1) was stirred at RT for 48 h. After removal of solvent, theresidue was purified by flash chromatography on a 35 cc column of silicagel. Elution with CHCl₃ :MeOH:NH₄ OH (95:5:0.5) afforded 67 mg ofmaterial which was further purified by trituration with Et₂ O to afford60 mg (63%) of the title Compound 298e as a white powder; m.p. 125°-126°C.; [α]_(D) =-3.4° (c 0.82, MeOH)

Mass Spec: (M+H)⁺ 681⁺

Analysis Calc. for C₃₇ H₅₂ N₄ O₈ ·0.87 H₂ O: C, 63.81; H, 7.78; N, 8.04.Found: C, 63.88; H, 7.53; N, 8.04.

EXAMPLE 299 Preparation of[1S-[1R*,2S*(2S*,3R*)]-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-(2-methoxyethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1-(hydroxymethyl)-1-methylethyl ester (Compound 299b)

(a) Compound 299a ##STR660##

To a solution of 200 mg (0.72 mmol) of Compound 175c, 113 μl (1.44 mmol)of 2-methoxyethanol and 377 mg (1.44 mmol) of PPh₃ in 3 ml of dry THF atRT, was added 226 μl (1.44 mmol) of DEAD. Stirring was continuedovernight. After removal of solvent, flash chromatography of the oilresidue on silica gel (25 % EtOAc-hexane) afforded 198 mg (81%) ofCompound 299a as a white solid.

(b) Compound 299b ##STR661##

Compounds 298c and 299a were reacted by a two-step procedure analogousto that used for the conversion of Compound 298c to Compound 298e togive the title Compound 299b (white solid).

m.p. 128°-130° C.; [α]_(D) =-4.0° (c 0.89, MeOH)

Mass Spec.: (M+H)⁺ 634⁺

Analysis Calc. for C₃₃ H₅₁ N₃ O₉ ·0.42 H₂ O: C, 61.81; H, 8.15; N, 6.55.Found: C, 61.88; H, 8.21; N, 6.48.

EXAMPLE 300 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-hydroxy-4-[4-(4-methoxybutoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 300d)

(a) Compound 300a ##STR662##

4-Penten-1-ol (1.80 ml; 17.5 mmol) was added dropwise over 1 h to asuspension of pentane washed NaH (770 mg 60% in oil; 19.2 mmol) in 35 mlof DMF at 0° C. After stirring at 0° C. for 30 min, methyl iodide (1.40ml; 21.8 mmol) was added dropwise over 15 min and the reaction mixturewas allowed to warm to RT. After stirring 18 h at RT, the excess methyliodide was pumped off (dry ice trap). H₂ O was then added and themixture was extracted with Et₂ O. The organic layer was washed with H₂ Oand brine, dried (MgSO₄) and most of the Et₂ O was removed atatmospheric pressure to give a concentrated solution of Compound 300a inEt₂ O which was used without further purification.

(b) Compound 300b ##STR663##

Compound 300a was converted to Compound 300b by a procedure analogous tothat of Example 277b.

(c) Compound 300c ##STR664##

Compounds 175c and 300b were reacted by a procedure analogous to that ofExample 282a to give Compound 300c.

(d) Compound 300d ##STR665##

Compounds 300c and 16b were reacted by a procedure analogous to that ofExample 226b to give the title Compound 300d (white solid).

m.p. 118°-125° C.; [α]_(D) =+1.4° (0.59, MeOH).

Mass Spec. FAB: M+H=646.

Analysis calc. for C₃₅ H₅₅ N₃ O₈ ·1.39 H₂ O: C, 62.67; H, 8.68; N, 6.26;Found: C, 62.50; H, 8.43; N, 6.43.

EXAMPLE 301 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-hydroxy-2-methylpropyl]carbamicacid, phenylmethyl ester, isomer A (Compound 301b)

(a) Compound 301a ##STR666##

Compound 239b was converted to Compound 301a by a procedure analogous tothat of Example 205a.

(b) Compound 301b ##STR667##

Compounds 301a and 54 were reactedby a procedure analogous to that ofExample 55 (DMF only used) to give the Compound 301b along with itsdiastereomer (at •) Compound 302. Flash chromatography (silica gel, 5 by10.5 cm), eluting with a step-wise gradient of MeOH:NH₄ OH:CH₂ Cl₂(5:0.5:94.5 to 8:0.8:91.2) followed by trituration of the faster movingisomer with hot Et₂ O gave the title Compound 301b (53 mg, 17% yield) asa colorless solid.

R_(f) =0.39 (10:1:89 MeOH:NH₄ OH:CH₂ Cl₂); m.p. 164°-166° C.; [α]_(D)=+7.89° (c 0.34, MeOH).

Anal. Calc. for C₃₈ H₅₂ N₄ O₈ ·0.58 H₂ O C, 64.90; H, 7.62; N, 7.97Found: C, 64.97; H, 7.55; N, 7.90

EXAMPLE 302 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-hydroxy-2-methylpropyl]carbamicacid, phenylmethyl ester, isomer B (Compound 302) ##STR668##

Flash chromatography of the diastereomeric mixture described in Example301 followed by trituration of the slower moving isomer with hot Et₂ Oand with hot EtOAc gave Compound 302 (48 mg, 15% yield) as a colorlesssolid. R_(f) =0.33 (10:1:89 MeOH:NH₄ OH:CH₂ Cl₂); m.p. 185°-189° C.;[α]_(D) =-17.3° (c 0.15, MeOH).

Anal. Calc. for C₃₈ H₅₂ N₄ O₈ ·0.26 H₂ O C, 65.44; H, 7.59; N, 8.03Found: C, 65.54; H, 7.53; N, 7.93

EXAMPLE 303 Preparation of [1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[[carbamic acid],1-(hydroxymethyl)cyclobutyl 1,1-dimethylethyl ester (Compound 303e)

(a) Compound 303a ##STR669##

Compound 303a was prepared as described in J. Am. Chem. Soc., 71, 3925(1949).

(b) Compound 303b ##STR670##

Compound 303a was converted to Compound 303b by a procedure analogous tothat of Example 277c.

(c) Compound 303c ##STR671##

Compounds 303b and 48 were converted to Compound 303c by a two-stepprocedure analogous to that used for the conversion of Compound 149c toCompound 149e (DMF was used in the coupling of thep-nitrophenylcarbonate of Compound 303b with Compound 48).

(d) Compound 303d ##STR672##

Compound 303c was converted to Compound 303d by a procedure analogous tothat of Example 162.

(e) Compound 303e ##STR673##

Compound 303d was converted to the title Compound 303e (light-brownsolid) by a three-step procedure analogous to that used for theconversion of Compound 289a to Compound 289d.

m.p. 139°-145° C.; [α]_(D) =-5.1° (c 0.2, CH₃ OH).

Mass Spec.(FAB) (M+H)⁺ =572

Analysis calc. for C₃₁ H₄₅ N₃ O₇ ·2.05H₂ O: C, 61.17; H, 8.13; N, 6.90;Found: C, 60.95; H, 7.70; N, 7.12.

EXAMPLE 304 Preparation of[1S-[1R*,2S*(2S,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-(3-pyridinyloxy)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 304c)

(a) Compound 304a ##STR674##

To a 0° C. suspension of 3-hydroxypridine (1.00 g; 10.5 mmol), Ph₃ P(7.08 g; 27.0 mmol), and bromoethanol (1.91 mL; 27.0 mmol) in anhydrousTHF (30 mL) was added dropwise DEAD (4.25 mL; 27.0 mmol) over 15 min,The resulting yellow solution was allowed to warm to RT and stirred for36 h, Volatiles were removed in vacuo to give a yellow-brown residue,which was dissolved in EtOAc and Et₂ O (1:1). This solution wasextracted with aqueous 1N HCl and the aqueous extracts basified at 0° C.with excess 1M aq, NaOH, Extraction with EtOAc followed by drying(MgSO₄) and evaporation in vacuo gave an oil which was purified onsilica gel (150 mL) using a stepwise gradient from 3:1 to 1:2hexanes:EtOAc to afford Compound 304a (1.27 g; 60%) as a yellow oil.

(b) Compound 304b ##STR675##

To a 0° C. suspension of NaH (0.032 g of a 60% suspension in oil) inanhydrous DMF (1.0 mL) was added dropwise a solution of Compound 175c(0.200 g; 0.716 mmol) in DMF (1.0 mL), The solution was stirred at RTfor 1 h, then recooled to 0° C. A solution of Compound 304a (0.167 g;0.827 mmol), n-Bu₄ NI (0.015 g; 0.039 mmol) and 15-crown-5 (0.159 mL;0.80 mmol) in DMF (1.0 mL) was added dropwise. The reaction was stirredat RT for 24 h. Volatiles were removed in vacuo, and the residue waspartitioned between H₂ O and EtOAc. The organic extracts were washedwith H₂ O, dried (Na₂ SO₄) and concentrated in vacuo to give an oil,which was purified on silica gel (100 mL) using a gradient from 3:1 to1:3 hexane:EtOAc as eluent to give Compound 304b (0.168 g; 59%) as awhite solid.

(c) Compound 304c ##STR676##

Compound 304b (0.160 g; 0.400 mmol) was reacted with Compound 16b (0.112g; 0.400 mmol) in DMF at 100° C. for 5 h. Volatiles were removed invacuo and the residue was chromatographed on silica gel (100 mL) usingas eluent a stepwise gradient from 99:1:0.1 to 90:10:1 CH₂ Cl₂ :MeOH:NH₄OH to afford a white solid (0.125 g, 46%). This material was furtherpurified by preparative HPLC on a C-18 column (6 μm- 30×300 cm; using astepwise gradient from 50:50 to 75:25 A:B; A=90:10:0.05 MeOH:H₂ O:TFA;B=90:10:0.05 H₂ O:MeOH:TFA) followed by basification with saturated aq.NaHCO₃, extraction with EtOAc, concentration and lyphilization fromdioxane-H₂ O to afford the title Compound 304c (0.091 g; 34%) as a whitesolid.

m.p.=127°-130° C.; [α]_(D) =-3.5° (c=0.34; MeOH)

Mass Spec. (CI): (M+H)⁺ =681;

Analysis calc. for C₃₇ H₅₂ N₄ O₈.0.80 H₂ O: C, 63.92; H, 7.77; N, 8.06Found: C, 64.24; H, 7.72; N, 7.74

EXAMPLE 305 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)probyl]-N²-[(dimethylamino)carbonyl)-3-methyl-L-valinamide (Compound 305b)

(a) Compound 305a ##STR677##

To a 0° C. solution of Compound 263b (0.271 g; 0.387 mmol) in anhydrousCH₂ Cl₂ (4.0 mL) was added dimethyl carbamyl chloride (0.050 g; 0.464mmol) dropwise, followed by dry Et₃ N (0.129 mL, 0.930 mmol). Thereaction was allowed to warm to RT and stirred for 24 h. Additionaldimethyl carbamyl chloride (0.040 g; 0.372 mmol) and Et₃ N (0.100 mL;0.718 mmol) were added and the reaction was stirred for another 24 h.Aqueous NaHCO₃ (10 mL of a 50% saturated solution) was added andextracted with CH₂ Cl₂. The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo to give an oil, which was chromatographedon silica gel (150 mL) with a stepwise gradient from 2:1 to 1:4hexanes:EtOAc to afford Compound 305a (0.193 g; 65%) as a white foam.

(b) Compound 305b ##STR678##

Compound 305a was converted to the title Compound 305b (white solid) bya procedure analogous to that of Example 21.

m.p.=146°-150° C. (dec.); [α]_(D) =-12.5° (c=0.20; MeOH).

Mass Spec. (FAB): (M+H)⁺ =628.

EXAMPLE 306 Preparation of[1S-[1R*,2S*(2S*,3R*)]-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-(2-hydroxypropoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 306e)

(a) Compound 306a ##STR679##

To a 0° C. suspension of THF-washed NaH (1.0 g of a 60% suspension inoil) was added dropwise a solution of methyl lactate (2.10 mL; 22.0mmol) in 10 mL of dry THF over 15 min. The reaction mixture was allowedto warm to 20° C. and stirred for 30 min. The solution was cooled to 0°C. and benzyl bromide (2.97 mL;25 mmol) in 5 mL of dry THF was added,followed by Bu₄ NI (0.092 g; 0.25 mmol). The reaction solution wasallowed to warm to RT and stirred for 24 h. The reaction mixture waspartitioned between H₂ O and EtOAc and the combined organic extractswere washed with H₂ O and brine and dried over Na₂ SO₄. Volatiles wereremoved in vacuo to give an oil, which was-purified on silica gel usinga gradient from hexane to 10% EtOAc/hexane to afford Compound 306a (2.46g; 57%) as a clear, colorless oil.

(b) Compound 306b ##STR680##

Compound 306a was converted to Compound 306b by a procedure analogous tothat of Example 281a (reaction was run at 0° C. to RT).

(c) Compound 306c ##STR681##

Compounds 306b and 175c were reacted by a procedure analogous to that ofExample 282a to give Compound 306c.

(d) Compound 306d ##STR682##

Compounds 306c and 16b were reacted by a procedure analogous to that ofExample 226b to give the Compound 306d.

(e) Compound 306e ##STR683##

To a suspension of 10% Pd/C (60 mg) in MeOH (2.5 mL) was added Compound306d (64 mg; 0.09 mmol) followed by aq. HCl (900 μL of a 0.1N solution)and the reaction was placed under an atmosphere of H₂. After 1 h, thereaction mixture was neutralized with 900 μL of 0.1N NaOH, filteredthrough a Celite plug and concentrated in vacuo. The crude product waspurified on silica gel using a stepwise gradient from 98:2:0.2 to92:8:0.8 CH₂ Cl₂ :MeOH: NH₄ OH to afford Compound 306e (35 mg; 65%) as awhite solid.

m.p.=145°-147° C.

Mass Spec. (CI): (M+H)=618

Analysis calc. for C₃₃ H₅₁ N₃ O₈ ·0.94 H₂ O C, 62.44; H, 8.40; N, 6.62C, 62.89; H, 8.17; N, 6.17

EXAMPLE 307 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]amino]carbonyl]-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-2.2-dimethylpropyl]carbamicacid, phenylmethyl ester, isomer A (Compound 307e)

(a) Compound 307a ##STR684##

To a solution of dihydro-4,4-dimethyl-2,3-furandione (0.5 g, 3.76 mmol)in HOAc (20 mL) was added KOAc (1.0 g, 0.01 mol) and then H₂ NOH.HCl(0.70 g, 0.01 mol). After 1.2 h, the reaction mixture was partitionedbetween EtOAc and H₂ O, and the aqueous layer extracted with EtOAc. Thecombined organic extracts were dried (Na₂ SO₄) and evaporated in vacuoto give Compound 307a (1.28 g, 89% yield) as a colorless solid.

(b) Compound 307b ##STR685##

A solution of Compound 307a (710 mg, 4.96 mmol) in EtOH (3 mL) was addedto a suspension of 180 mg of 5% Pd/C in EtOH(10 mL) and 2N HCl (5 mL)and the mixture stirred under a H₂ atmosphere. After 4 h, the reactionmixture was filtered through a Nylon plug and the filtrate evaporated invacuo to give Compound 307b (826 mg, ≦100% crude yield) as an oily solidafter co-evaporation from MeOH.

(c) Compound 307c ##STR686##

To a 0° C. solution of Compound 307b (≦0.82 g, ≦3.47 mmol) in aqueous0.83M NaHCO₃ (10 mL) was added Cbz-Cl (0.50 mL, 3.26 mmol). After 15min, the reaction mixture was brought to RT for 3 h and a second portionof Cbz-rCl (0.10 mL, 0.65 mmol) was added. After a total of 5 h, thereaction mixture was filtered, washing the solid with H₂ O and hexanes.The solid residue was purified by flash chromatography (silica gel, 5 by10 cm), eluting with 2% EtOAc:CH₂ Cl₂ to give Compound 307c (567 mg, 61%yield for the 2 steps) as a colorless solid.

(d) Compound 307d ##STR687##

To a solution of Compound 307c (500 mg, 1.90 mmol) in THF (15 mL) wasadded an aqueous solution of LiOH (80 mg, 1.91 mmol). After 1.45 h thevolatiles were evaporated in vacuo to give the lithium salt (826 mg,≦100% crude yield) as an oily solid after co-evaporation with dry THFand with dry DMF. The crude residue (≦1.90 mmol) was dissolved in DMF (7mL) and imidazole (320 mg, 4.7 mmol) and then t-butyldimethylsilylchloride (630 mg, 4.18 mmol) was added. After stirring 23 h, MeOH (8 mL)was added and the mixture was stirred for 21 h, then stored at -80° C.After warming, the volatiles were removed in vacuo and the oily residuewas partitioned between EtOAc and saturated NH₄ Cl. The combined organicextracts were dried over Na₂ SO₄ and concentrated in vacuo to give anoil which was purified by flash chromatography (silica gel, 5 by 9 cm),eluting with EtOAc:CH₂ Cl₂ (6, 7 and then 20% EtOAc containing 1% AcOH)to give Compound 307d (450 mg, 60% yield for the 2 steps) as an oilysolid after co-evaporation with heptane.

(e) Compound 307e ##STR688##

To a solution of Compound 307d (345 mg, 0.873 mmol) and Compound 54 (410mg, 0.925 mmol) in DMF (6 mL) at 0° C. under argon was added HOBT (190mg, 1.41 mmol), EDCI (170 mg, 0.887 mmol), and then N-methylmorpholine(0.1 mL, 0.91 mmol). The mixture was allowed to come to RT and stirredfor 20 h. The reaction mixture was partitioned between EtOAc andsaturated NaHCO₃, and the combined organic extracts were washed withbrine, dried over Na₂ SO₄ and evaporated in vacuo to leave an oil. Theresidue was purified by flash chromatography (silica gel, 5 by 10 cm),eluting with a gradient of MeOH:NH₄ OH:CH₂ Cl₂ (2:0.2:97.8, 3:0.3:96.7,3.5:0.35:96.15, 4:0.4:95.6, 4.5:0.45:95.05, 0 5:0.5:94.5, and then6:0.6:93.4) to give the title Compound 307e (170 mg, 47%) as a colorlessglass (single isomer). R_(f) (SiO₂)=0.45 (10:1:89 MeOH:NH₄ OH:CH₂ Cl₂);Compound 309a was also isolated.

EXAMPLE 308 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-(hydroxymethyl)-2-methylpropyl]carbamicacid, phenylmethyl ester, isomer A (Compound 308) ##STR689##

A solution of Compound 307e (162 mg, 0.197 mmol) in AcOH:THF:H₂ O (5 mL,3:1:1) was stirred at RT for 59.5 h and the volatiles were removed invacuo. The oily residue was co-evaporated once with heptane and thentwice with heptane/CH₂ Cl₂ to leave an oily solid residue. The residuewas purified by flash chromatography (silica gel, 2.5 by 18 cm), elutingwith MeOH:NH₄ OH:CH₂ Cl₂ (6:0.6:93.4 and then 7:0.7:92.3) to give thetitle Compound 308 (98 mg, 70%) as a colorless solid.

R_(f) (SiO₂)=0.29 (10:1:89 MeOH:NH₄ OH:CH₂ Cl₂); m.p. 68°-70° C.;[α]_(D) =-19.8° (c 0.19, MeOH).

(FAB): 707 (M+H).

Analysis Calc. for C₃₉ H₅₄ N₄ O₈ ·0.46 H₂ O: C, 65.51; H, 7.74; N, 7.83Found: C, 65.45; H, 7.62; N, 7.89

EXAMPLE 309 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-(hydroxymethyl)-2-methylpropyl]carbamicacid, phenylmethyl ester, isomer B (Compound 309b)

(a) Compound 309a ##STR690##

Flash chromat, ography o#the reaction mixture from Example 307e gaveCompound 309a, the diastereomer at • of Compound 307e. R_(f) (SiO₂)=0.43(10:1:89 MeOH:NH₄ OH:CH₂ Cl₂).

(b) Compound 309b ##STR691##

Compound 309a was converted to the title Compound 309b (colorless solid)by a procedure analogous to that, of Example 308.

R_(f) (SiO₂)=0.35 (10:1:89 M:eOH:NH₄ OH:CH₂ Cl₂); m.p. 72°-76° C.;[α]_(D) =-9.72° (c 0.26, ACOH).

Mass Spec.: (FAB): 707 (M+H).

Anal. Calc. for C₃₉ H₅₄ N₄ O₈ ·0.47 H₂ O: C, 65.49; H, 7.74; N, 7.83Found: C, 65.50; H, 7.64; N, 7.82

EXAMPLE 310 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)3,1-propanediyl]]bis[carbamicacid], 3-tetrahydrofuranyl 1,1-dimethylethyl ester (Compound 310)##STR692##

3-Hydroxytetrahydrofuran and Compound 48 were reacted by a three-stepprocedure analogous to that used for the conversion of Compound 149c toCompound 150 (DMF was used in the coupling of the p-nitrophenylcarbonatewith Compound 48) to give the title Compound 310 (white solid).

m.p. 200°-203° C.; [α]_(D) =-11° (c=0.2, CH₃ OH)

Analysis calc. for C₃₀ H₄₃ N₃ O₇ ·0.26 H₂ O: C, 63.84; H, 8.13; N, 7.44Found: C, 63.89; H, 7.70; N, 7.39

EXAMPLE 311 Preparation of[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]aminocarbonyl]propyl]carbamicacid, (2-auinoxalinyl)methyl ester (Compound 311c)

(a) Compound 311a ##STR693##

A solution of 2-hydroxymethyl quinoxaline (Lindquist, J. Chem. Soc.,2052-8 (1956)) (160.2 mg, 1.0 mmol) in 4 ml of CH₂ Cl₂ was cooled to 0°C. and pyridine (87 mg, 1.1 mmol) was added followed by the addition ofp-nitrophenylchloroformate (222 mg, 1.1 mmol) in 2 ml of CH₂ Cl₂. Themixture was stirred at 0° C. for 3 h and slowly warmed to RT and stirredovernight. The reaction was diluted with EtOAc and washed with H₂ O andbrine. After drying over Na₂ SO₄ the solvents were evaporated yieldingthe crude product as a yellow solid. The product was purified bychromatography on CC-7 (buffered silica, pH 6.8) eluting withEtOAc/hexane (1:1) to afford 304 mg (93%) of Compound 311a as acolorless solid.

(b) Compound 311b ##STR694##

L-tert-Leucine (112 mg, 0.85 mmol) was dissolved in 0.85 ml of 1N NaOHand a solution of Compound 311a (275 mg, 0.85 mmol) in 1.5 ml of dioxanewas added at RT followed by the addition of Et₃ N (91 mg, 1.55 mmol).The reaction was stirred overnight, diluted with 5% KHSO₄ and extractedwith EtOAc. The combined EtOAc extracts were washed with H₂ O and brineand the solvents evaporated yeilding the crude product as a plae yellowsolid. The crude material was purified ona silica column eluting with5-10% MeOH/CH₂ Cl₂ to afford 198 mg (73%) of the Compound 311b as acolorless solid.

(c) Compound 311c ##STR695##

A mixture of Compound 54 (273 mg, 0.6 mmol), Compound 311b (195 mg, 0.6mmol) and HOBT (94 mg, 0.6 mmol) was dissolved in 2 ml of dry DMF andthe mixture cooled to 0° C. EDCI (118 mg, 0.6 mmol) was added and themixture stirred at 0° C. for 3 h and then slowly allowed to warm to RTand stir overnight. The reaction was diluted with EtOAc and washed with5% KHSO₄, NaHCO₃, H₂ O and brine. The solvents were evaporated and thecrude residue was pruified ona silica column eluting with 3-5% MeOH/CH₂Cl₂ +0.1% NH₄ OH to afford 198 mg (44%) od the title Compound 311c as acolorless solid.

m.p. 178°-184° C. (dec); [α]_(D) =14.5° (c=0.25, MeOH).

Mass Spec. (FAB): (M+H)⁺ =743⁺

Analysis Calcd. for C₁₄ H₅₄ N₆ O₇ ·0.45 H₂ O: C, 65.58 H, 7.37 N, 11.1Found C, 65.62 H, 7.41 N, 11.15

EXAMPLE 312 Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-(1,1-Dimethylethyl)-4-hydroxy-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A (Compound 312d)

(a) Compound 312a ##STR696##

Compound 312a was prepared as described in Chem. Ber. 123, 2167-2172(1990).

(b) Compound 312b ##STR697##

Compound 312a was converted to Compound 312b by a procedure analogous tothat of Example 291b.

(c) Compound 312c ##STR698##

To a 5° C. mixture of Compound 312b (250 mg, 0.91 mmol) and HOBT hydrate(149 mg, 1.1 mmol) in CH₂ Cl₂ (1 mL ) and DMF (0.5 mL ) was added EDCIhydrochloride (192 mg, 1.0 mmol). The mixture was allowed to warm to RTand was stirred overnight. The mixture was concentrated to remove mostof the DMF and the residue was partitioned between EtOAc and sat'd. aq.NaHCO₃. The combined organic extracts were washed with H₂ O and brine,dried (Na₂ SO₄) and concentrated to afford a crude residue which waspurified by column chromatography on silica gel eluting withEtOAc-hexane (80-20) to afford 324 mg (91% yield) of Compound 312c as awhite solid.

(d) Compound 312d ##STR699##

A mixture of Compound 54 (365 mg, 0.82 mmol) and Compound 312c (269 mg,0.69 mmol) in 1.2 mL dry DMF was heated at 75°-80° C. for 4 hr. Themixture was cooled to RT and concentrated to remove most of the DMF.This residue was dissolved in EtOAc and the solution was washed withsat'd. aq. NaHCO₃, H₂ O, and brine, and was dried over Na₂ SO₄. Thesolution was concentrated to afford 600 mg of a semisolid which wasdissolved in 3 mL THF and 3 mL H₂ O followed by the addition of 9 mLHOAc. The clear solution was stirred overnight at RT. The reactionmixture was concentrated and the crude product was purified bychromatography on silica gel eluting with a gradient of CH₂ Cl₂-MeOH-aq. NH₄ OH (98:1.8:0.2 to 92:7.2:0.8) to afford the semipurediastereomers (at *) Compounds 312d and 313. The faster movingdiastereomer was repurified by preparative TLC on silica gel elutingwith CH₂ Cl₂ -MeOH-aq. NH₄ OH (90:9:1) to afford 57 mg (14% yield) ofthe title Compound 312d (white solid).

TLC R_(f) (SiO₂)=0.19 (CH₂ Cl₂ -MeOH-aq. NH₄ OH 90:9:1);

m.p. 158°-162° C. ("softening" at 150°-157° C.); [α]_(D) =-0.57°;(C=1.23, CH₃ OH)

Mass Spec. (FAB), 586 (M+H⁺)

Analysis calc. for C₃₃ H₅₁ N₃ O₆ ·0.05H₂ O: C, 67.56; H, 8.78; N, 7.16;Found: C, 67.45; H, 8.69; N, 7.27.

EXAMPLE 313 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-(1,1-Dimethytethyl)-4-hydroxy-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer B (Compound 313) ##STR700##

Compound 313 (white solid) was prepared as the slower moving isomer asdescribed in Example 312.

TLC R_(f) (SiO₂)=0.13 (CH₂ Cl₂ -MeOH-aq. NH₄ OH 90:9:1);

mp 140°-143° C.; [α]_(D) =-5.62°; (c=1.30, CH₃ OH)

Mass Spec. (FAB), 586 (M+H⁺)

Analysis calc. for C₃₃ H₅₁ N₃ O₆ ·0.52H₂ O: C, 66.61; H, 8.81; N, 7.06;Found: C, 66.53; H, 8.87; N, 7.14.

EXAMPLE 314 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-promanediyl]]bis[carbamicacid], 1,1-dimethylethyl-3-methyl-3-tetrahydrofuranyl ester (Compound314c)

(a) Compound 314a ##STR701##

To the suspension of pyridinium chlorochromate (32 g, 0.15 mol) andactivated 4 Å molecular sieves (40 g, powder) in 200 ml of dry CH₂ Cl₂cooled at 10° C. was added a solution of 3-hydroxytetrahydrofuran (8.9g, 0.1 mol) in 50 ml of dry CH₂ Cl₂. The mixture was stirred at RT for2.5 h and then filtered through a short column of Florisil. The filtratewas evaporated by careful distillation of the solvent. Short-pathdistillation of the residue (bp: 136°-137° C.) afforded 4.9 g (56%) ofCompound 314a as a colorless liquid.

(b) Compound 314b ##STR702##

Compound 314a was converted to Compound 314b by a procedure analogous tothat of Example 258a.

(c) Compound 314c ##STR703##

Compounds 314b and 48 were converted to the title Compound 314c (whitesolid) by a three-step procedure analogous to that used for theconversion of Compound 149c to Compound 150 (DMF was used in thecoupling of the p-nitrophenyl carbonate of Compound 314b with Compound48).

m.p.: 166°-167° C.

Mass Spec. (FAB): 572⁺ (M+H)⁺.

Analysis Calc. for C₃₁ H₄₅ N₃ O₇.0.18H₂ O: C, 64.75; H, 7.95; N, 7.31.Found: C, 64.77; H, 8.00; N, 7.29.

EXAMPLE 315 Preparation of[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamicacid, (2-oxo-4-oxazolidinyl)methyl ester (Compound 315b)

(a) Compound 315a ##STR704##

To a stirring solution of 2-amino-1,3-propanediol (1.58 g, 0.017 mol) inaqueous 1.73M KOH at 0° C. (20 mL) was added a toluene solution ofphosgene (11 mL, 0.021 mol). After warming to RT slowly overnight, thereaction mixture was extracted with hexanes and the aqueous layerevaporated at -30° C. to give an oily solid residue. The residue wasrepeatedly washed with hot EtOAc and the combined washes were evaporatedin vacuo. The resulting solid residue was co-evaporated with heptane toafford Compound 315a as a colorless solid (1.28 g, 63%).

(b) Compound 315b ##STR705##

tert-Leucine and Compounds 315a and 54 were reacted by a three-stepprocedure analogous to that used for Example 257a through 257c to givethe title Compound 315b (colorless solid).

m.p. 104°-114° C.; [α]_(D) =-16.6° (c 0.22, MeOH).

Mass Spec.: (FAB): 700 (M+H).

Analysis Calc. for C₃₆ H₅₃ N₅ O₉ : C, 61.78; H, 7.63; N, 10.01 Found: C,61.62; H, 7.91; N, 9.65.

EXAMPLE 316 Preparation of [1S-(1R*,2S*),(3S-trans)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[carbamicacid], 4-hydroxy-3-tetrahydrofuranyl 1,1-dimethylethyl ester (Compound316) ##STR706##

1,4-Anydro-L-threitol was converted to its mono-p-nitrophenyl carbonatewhich was reacted with Compound 48 by a procedure analogous to that usedfor the conversion of Compound 149c to 150 (DMF was used in the couplingof the p-nitrophenyl carbonate with Compound 48) to give the titleCompound 316 (white solid).

m.p.: 183°-184° C.; [α]₃₆₅ =-27.2° (c 0.2, MeOH)

Mass Spec. (FAB): 574⁺ (M+H)⁺.

Analysis Calc. for C₃₀ H₄₃ N₃ O₈ : C, 62.81; H, 7.55; N, 7.32. Found: C,62.77; H, 7.72; N, 7.25.

EXAMPLE 317 Preparation of [1S-(1R*,2S*),(3R-trans)]-[Iminobis[2-hydroxy-11-(phenylmethyl)-3,1-propanediyl]]bis[carbamicacid], 4-hydroxy-3-tetrahydrofuronyl 1,1-dimethylethl ester (Compound317) ##STR707##

1,4-Anydro-D-threitol (prepared from D-threitol [Terfort, Synthesis, 951(1992)] according to Otey et al., J. Org. Chem., 26, 1673 (1961)) wasconverted to its mono-p-nitrophenyl carbonate which was reacted withCompound 48 by a procedure analogous to that used for the conversion ofCompound 149c to 150 (DMF was used in the coupling of the p-nitrophenylcarbonate with Compound 48) to give the title Compound 317 (whitesolid).

m.p.: 181°-182° C.; [α]_(D) =-31.3° (c 0.63, MeOH).

Mass Spec. (FAB): 574⁺ (M+H)⁺.

Analysis Calc. for C₃₀ H₄₃ N₃ O₈.0.45 H₂ O: C, 61.93; H, 7.61; N, 7.22.Found: C, 62.01; H, 7.55; N, 7.14.

EXAMPLE 318 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]bis[carbamicacid], 1,1-dimethylethyl-3-tetrahydropyranyl ester (Compound 318)##STR708##

3-Hydroxytetrahydropyran (Zweifel et al., J. Org. Chem., 35, 898-902(1970)) and Compound 48 were reacted by a procedure analogous to thatused for the conversion of Compound 149c to 150 (DMF was used in thecoupling of the p-nitrophenyl carbonate with Compound 48) to give thetitle Compound 318 (colorless solid).

m.p. 185°-187° C.; [α]_(D) =-1.80° (c 0.36, CHCl₃).

MS: (FAB): 572 (M+H).

Anal. Calc. for C₃₁ H₄₅ N₃ O₇ . 0.09 H₂ O C, 64.95; H, 7.94; N, 7.35Found: C, 64.68; H, 8.00; N, 7.33.

EXAMPLE 319 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)3,1-propanediyl)]bis[carbamicacid], 1,1-dimethylethyl 4-oxetanyl ester (Compound 319c)

(a) Compound 319a ##STR709##

Compound 319a was prepared as described in Baum et al., J. Org. Chem.,48, 2953-2956 (1983).

Compound 319b ##STR710##

To a solution of Compound 319a (670 mg, 4.58 mmol) in MeOH (7 mL) wasadded pyridinium p-tosylate (277 mg, 5 mmol). After 4 h NaHCO₃ (150 mg)was added and the volatiles were evaporated in vacuo to give an oilysolid residue which was purified by flash chromatography (silica gel, 3by 15 cm), eluting with MeOH:CH₂ Cl₂ (3 and then 3.5% MeOH) to giveCompound 319b (148 mg, 44%) as an oil.

(c) Compound 319c ##STR711##

Compounds 319b and 48 were reacted by a procedure analogous to that usedfor the conversion of Compound 149c to 150 (DMF was used in the couplingof the p-nitrophenyl carbonate with Compound 48) to give the titleCompound 319c (colorless solid).

m.p. 196°-199° C.; [α]_(D) =-9.06° (c 0.23, MeOH).

Mass Spec.: (FAB): 544 (M+H).

Analysis Calc. for C₂₉ H₄₁ N₃ O₇ : C, 64.07; H, 7.60; N, 7.73 Found: C,63.99; H, 7.74; N, 7.63.

EXAMPLE 320 Preparation of[S-[1R*,2S*,(2S*,3R*)]-[2,2-Dimethyl-1-[[[3-[[3-(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]methylcarbamicacid, methyl ester (Compound 320c)

(a) Compound 320a ##STR712##

Compound 246a was converted to Compound 320a by a procedure analogous tothat of Example 66a.

(b) Compound 320b ##STR713##

Compound 320a was converted to Compound 320b by a procedure analogous tothat of Example 70c (no acid work-up).

(c) Compound 320c ##STR714##

Compounds 320b and 54 were reacted by a procedure analogous to that ofExample 93f to give the title Compound 320c (white solid).

m.p.=78°-81° C.

Mass Spec. (CI): (M+H)=629

Analysis Calc. for C₃₄ H₅₂ N₄ O₇ . 1.35 H₂ O: C, 62.52; H, 8.44; N, 8.58Found: C, 62.74; H, 8.27; N, 8.36.

EXAMPLE 321 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2,2-Dimethyl-1-hydroxycyclopentyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A (Compound 321d)

(a) Compound 321a ##STR715##

A suspension of anhydrous cerium (III) chloride (4.25 g; 17 mmol) infreshly distilled THF was stirred at RT for 2 h. After cooling thissuspension to -78° C., vinylmagnesium bromide (17 ml 1.0M in THF; 17mmol) was added dropwise over ˜15 min. The resulting light orangesuspension was stirred at -78 ° C. for 1.5 h. After this time2,2-dimethylcyclopentanone (1.27 g; 11 mmol) was added and the reactionmixture was stirred for 1.5 h at -78° C. Saturated NH₄ Cl solution (50ml) was added and the mixture was allowed to warm to RT with stirring.The mixture was partitioned between Et₂ O and H₂ O. The organic layerwas washed with H₂ O and brine, dried (MgSO₄), and most of the solventremoved in vacuo to afford 3.38 g of a light yellow liquid. This liquidwas ˜50% by wt. a solution of Compound 321a in THF and was used in thesubsequent step without further purification.

(b) Compound 321b ##STR716##

Ozone/oxygen was bubbled through a solution of Compound 321a (1.6 g; 50%by wt. in THF; 5.6 mmol) and NaHCO₃ (42 mg) in 50 ml of MeOH at -78° C.for ˜10 min. After purging the solution for 15 min, Me₂ S (4.5 ml) wasadded. After warming to RT, the mixture was stirred for 1 h and thevolatiles removed in vacuo. The residue was partitioned between Et₂ Oand H₂ O and the organic layer washed with brine and dried (MgSO₄).Concentration afforded 760 mg (96%) of Compound 321b as a colorlessliquid.

(c) Compound 321c ##STR717##

Sodium chlorite (746 mg; 6.6 mmol; 80% pure) was added to a rapidlystirring mixture of Compound 321b (720 mg; 5.06 mmol) and sulfamic acid(641 mg; 6.6 mmol) in 5 ml of H₂ O and 5 ml of THF at 0° C. Afterstirring at 0° C. for 30 min, 0.5 ml of Me₂ S was added followed by 20ml of 1N NaOH. This mixture was extracted with Et₂ O and the aqueouslayer acidified to pH ˜1.5 with saturated KHSO₄, saturated with NaCl,and extracted with EtOAc. The combined organic extracts were washed withbrine and dried (MgSO₄). Concentration afforded a solid which wasrecrystallized from hexane to afford 456 mg (57%) of Compound 321c as acolorless solid.

(b) Compound 321d ##STR718##

BOP-reagent (265 mg; 0.60 mmol) was added in one portion to a solutionof Compound 321c (90 mg; 0.569 mmol), Compound 54 (252 mg; 0.569) andN-methylmorpholine (66 μl; 0.60 mol) at 0° C. in 1 ml of DMF. Thereaction mixture was allowed to warm to RT and stir 16 h. After dilutingwith EtOAc, the organic phase was washed with H₂ O, saturated aq. NaHCO₃and brine. After drying (MgSO₄), the solvent was removed in vacuo. Theresidue was chromatographed on a 5×12 cm silica gel column eluting with2% MeOH/CH₂ Cl₂ followed by a gradient of 3-7% MeOH/CH₂ Cl₂ +0.3-0.7%NH₄ OH in 0.5% and 0.05% increments respectively. The slower movingisomer (at *) was rechromatographed on a 2.5×15 cm silica gel columnwith elution as above followed by trituration with Et₂ O which afforded23 mg (7%) of Compound 321d as a white solid.

R_(f) =0.25, CH₂ Cl₂ :MeOH:NH₄ OH, 90:9:1 (UV and PMA detection); m.p.108°-111° C.; [α]_(D) =-15.2° (c 0.25, MeOH).

Mass Spec. FAB: M+H=584.

Analysis calc. for C₃₃ H₄₉ N₃ O₆.0.57 H₂ O: C, 66.73; H, 8.51; N, 7.07;Found C, 66.66; H, 8.44; N, 7.14.

EXAMPLE 322 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2,2-Dimethyl-1-hydroxycyclopentyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer B (Compound 322) ##STR719##

The faster moving isomer from Example 321d was rechromatographed on a2.5×25 cm silica gel column using 1% MeOH/CH₂ Cl₂ followed by 2%MeOH/CH₂ Cl₂ then 2.5% MeOH/CH₂ Cl₂ and finally a gradient of 3-5%MeOH/CH₂ Cl₂ +0.3-0.5% NH₄ OH in 0.25% and 0.025% incrementsrespectively. Concentration and trituration with Et₂ O afforded 41 mg(12%) of Compound 322 as a white solid.

R_(f) =0.28, CH₂ Cl₂ :MeOH:NH₄ OH, 90:9:1 (UV and PMA detection); m.p.185°-190° C.; [α]_(D) =+15.5° (c 0.33, MeOH).

Mass Spec. FAB: M+H=584.

Analysis calc. for C₃₃ H₄₉ N₃ O₆.1.17 H₂ O: C, 65.53; H, 8.56; N, 6.95;Found C, 65.45; H, 8.25; N, 7.03.

EXAMPLE 323 Preparation of[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamicacid, (2-furo[3,2-b]pyridinyl)methyl ester (Compound 323f)

(a) Compound 323a ##STR720##

Compound 323a was prepared as described in Shiotani et al., J. Het.Chem., 23, 665 (1986).

(b) Compound 323b ##STR721##

Compound 323a was converted to Compound 323b by the method described inMorita et al., J. Heter. Chem. 24, 373, (1987).

(c) Compound 323c ##STR722##

To a solution of Compound 323b (1.5 g, 10.195 mmol) in 100 mL of 3:3:4THF-EtOH-CHCl₃ cooled to 0° C. was added NaBH₄ (0.675 g, 17.841 mmol) inportions. After the addition was complete, the mixture was stirred at 0°C. for 30 min, diluted with H₂ O and extracted with CH₂ Cl₂. Thecombined extracts were dried (MgSO₄) and concentrated. The crude residuewas flash chromatographed on silica gel eluting with a stepwise gradientof 25% to 100% EtOAc-hexane to afford Compound 323c (1.42 g, 93%) as abeige solid.

(d) Compound 323d ##STR723##

To a solution of Compound 323c (0.745 g, 5 mmol) in 30 mL of CH₂ Cl₂cooled to 0° C. was added 2 mL of pyridine followed byp-nitrophenylchloroformate (1.008 g, 5 mmol) as a solid. The reactionmixture was stirred for 16 h at RT, diluted with EtOAc and washed withsat. NaHCO₃ and brine. The organic phase was dried (MgSO₄) andconcentrated to obtain Compound 323d (1.56 g, 99%; crude yield)containing traces of p-nitrophenylchloroformate and p-nitrophenol.

(e) Compound 323e ##STR724##

Compound 323d (0.75 g; 2.38 mmol) in 5 mL of dioxane was added to asolution of L-tert-leucine (0.314 g; 2.38 mmol) in 2.4 mL of 1N NaOH atRT followed by the addition of Et₃ N (365 μL; 2.62 mmol). After 5 h atRT, the reaction mixture was diluted with 10% KHSO₄ and extracted withEtOAc. The organic extracts were washed with H₂ O and brine, dried(MgSO₄) and concentrated. Flash chromatography on silica gel of thecrude residue (CH₂ Cl₂ followed by 5% then 10% MeOH/CH₂ Cl₂ +0.5% HOAc)afforded 0.28 g (38%) of Compound 323e as a beige solid.

(f) Compound 323f ##STR725##

To a 0° C. solution of Compound 323e (0.173 g; 0.56 mmol) in 3 mL of CH₂Cl₂ was added HOBT (0.115 g; 0.84 mmol) followed by EDCI (0.114 g; 0.59mmol). After 30 min, Compound 54 (0.25 g; 0.56 mmol) was added followedby 0.5 mL of DMF. The reaction mixture was stirred at 0° C. for 30 minand at RT for 40 h, at which time it was diluted with CH₂ Cl₂, andwashed with H₂ O, sat. aq. NaHCO₃ and brine. The organic extracts weredried (MgSO₄), concentrated, and the resulting residue purified by flashchromatography on silica gel, eluting with a gradient of 98.9:1:0.1 to89:10:1 CH₂ Cl₂ :MeOH:NH₄ OH, to afford 0.26 g (65%) of the titleCompound 323f as a white solid.

m.p. 108°-112° C. (softening at 95°-105° C.); [α]_(D) =-16.5° (c=0.2,CH₃ OH).

Mass Spec. (FAB) (M+H)⁺ =732

Analysis calc. for C₄₀ H₅₃ N₅ O₈ . 1.77 H₂ O: C, 62.91; H, 7.46; N,9.17; Found: C, 62.91; H, 7.17; N, 9.17.

EXAMPLE 324 Preparation of1S-(1S*,2R*)-N,N'-Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bis(imino)bis[1-(1,1-dimethylethyl)-2-oxo-2,1-ethanediyl]]biscarbamicacid, dimethyl ester (Compound 324) ##STR726##

Compounds 74 and 246a were reacted by a procedure analogous to that ofExample 75f to give the title Compound 324 (colorless solid).

m.p. 98°-102° C.; [α]_(D) =-37.7° (c 0.25, CHCl₃).

Mass Spec.: (FAB): 686 (M+H).

Anal. Calc. for C₃₆ H₅₅ N₅ O₈ . 0.73 H₂ O C, 61.86; H, 8.14; N, 10.02Found: C, 61.86; H, 8.09; N, 10.06

EXAMPLE 325 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[(2-methoxy-3,3-dimethyl-1-oxobutyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 325b)

(a) Compound 325a ##STR727##

Through a solution of 4,4-dimethyl-3-methoxy-1-pentene (J. Am. Chem.Soc., 109, 3353, (1987); 0.512 g, 4 mmol) in 10 mL of CH₂ Cl₂ cooled to-78° C. was bubbled O₃ for a period of 2 h until a light blue colorpersisted. To the mixture was added Me₂ S (1.468 mL, 20 mmol) and theyellow solution stirred at RT for 2 h at which point most of the solventwas distilled off. The resulting aldehyde was then converted to Compound325a by a procedure analogous to that of Example 262e.

(b) Compound 325b ##STR728##

Compounds 325a and 54 were reacted by a procedure analogous to that ofExample 55 to give the title Compound 325b (white solid).

m.p. 153°-162° C.;

Mass Spec. (FAB) (M+H)⁺ =572

Analysis calc. for C₃₂ H₄₉ N₃ O₆.0.58 H₂ O: C, 66.02; H, 8.68; N, 7.22;Found: C, 65.99; H, 8.56; N, 7.25.

EXAMPLE 326 Preparation of[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamicacid, (2-phenyloxy)ethyl ester (Compound 326) ##STR729##

2-Phenoxyethanol was converted to its p-nitrophenyl carbonate which wasreacted with tert-leucine and the resulting product coupled withCompound 54 by a three-step procedure analogous to that used for Example257a through 257c to give the title Compound 326 (colorless solid).

m.p. 138°-140° C. (shrinks 120° C.); [α]_(D) =-20.4° (c 0.3, CHCl₃).

Mass Spec.: (FAB): 721 (M+H).

Anal. Calc. for C₃₆ H₅₃ N₅ O₉ . 0.31 H₂ O C, 66.13; H, 7.86; N, 7.71Found: C, 66.09; H, 7.85; N, 7.75.

EXAMPLE 327 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-(2-pyridinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-phenylmethyl)propyl]-N²-(methoxycarbonyl)-3-methyl-L-valinamide (Compound 327c)

(a) Compound 327a ##STR730##

To an ice cooled solution, under argon, of 608 mg (2.5 mmol) of Compound298a, 520 mg (2.75 mmol) of Compound 246a, 371 mg (2.75 mmol) of HOBTand 905 μl of N-methylmorpholine in 12.5 ml of DMF was added 528 mg(2.75 mmol) of EDCI. Stirring was continued with cooling for 1 h, thenat RT overnight. The solution was evaporated to dryness (30° C., highvacuum) and the residue taken into EtOAc and washed with brine, 1N HCl,brine, sat. NaHCO₃, and brine. After drying (MgSO₄), removal of solventafforded 1.03 g of Compound 327a as a solid white foam.

(b) Compound 327b ##STR731##

A solution of 250 mg (0.66 mmol) of Compound 327a in 8 ml of EtOH,containing 25 mg of 10% Pd on carbon catalyst, was stirred under anatmosphere of H₂ for 4 h. After removal of catalyst by filtrationthrough Celite, removal of solvent gave a solid foam residue which wasrecrystallized from CHCl₃ to afford 108 mg (47% yield over 2 steps) ofCompound 327b as a white powder.

(c) Compound 327c ##STR732##

A solution of 246 mg (0.70 mmol) of Compound 327b and 250 mg (0.65 mmol)of Compound 282a in 1 ml of DMF, under argon, was heated at 100° C. for5 h. The solvent was removed (30° C., high vacuum) and the residuepurified by flash chromatography on a 130 cc column of silica gel.Elution with CHCl₃ :MeOH:NH₄ OH (95:5:0.5) followed by recrystallizationfrom hot EtOAc afforded 170 mg of Compound 327c as a white solid.

m.p. 139°-141° C.; [α]_(D) =-15.9° (c 0.92, MeOH)

Mass Spec.: (M+H)⁺ 736⁺

Analysis Calc. for C₄₀ H₅₇ N₅ O₈ . 0.46 H₂ O: C, 64.56; H, 7.84; N,9.41. Found: C, 64.82; H, 7.87; N, 9.41.

EXAMPLE 328 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]-2-oxo-1-(trifluoromethyl)ethyl]carbamicacid, phenylmethyl ester (Compound 328b)

(a) Compound 328a ##STR733##

Compound 328a was prepared from D,L-trifluoromethyl alanine by aprocedure analogous to that of Example 85a.

(b) Compound 328b ##STR734##

Compounds 328a and 48 were reacted by a two-step procedure analogous tothat used for the conversion of Compound 48 to 52 to give the titleCompound 328b (white solid).

m.p. 166°-169° C.; [α]_(D) =-5.7° (c=0.21, CH₃ OH)

Analysis calculated for: C₃₆ H₄₅ N₄ O₇ F₃ . 1.21 H₂ O C, 59.68; H, 6.60;N, 7.73; F, 7.87 Found: C, 59.74; H, 6.47; N, 7.67; F, 7.81

EXAMPLE 329 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1-Amino-2,2,2-trifluoroethyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 329) ##STR735##

Compound 328b was converted to the title Compound 329 by a procedureanalogous to that of Example 19.

m.p. 152°-155° C.

EXAMPLE 330 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-hydroxy-3-[[2-hydroxy-3-[[(tetrahydro-3-hydroxy-3-furanyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 330b)

(a) Compound 330a ##STR736##

To a solution of Compound 314a (2.02 g, 23.46 mmol) in CH₂ Cl₂ (2.5 mL)was added trimethylsilyl cyanide (4.06 mL, 30.50 mmol), ZnI₂ (0.22 g,0.70 mmol) and the solution stirred at RT for 18 h. The reaction mixturewas purged with a stream of nitrogen, concentrated in vacuo and taken inconcentrated HCl (6 mL) and heated at reflux for 2 h. After cooling toRT, the mixture was saturated with Na₂ SO₄ and extracted with EtOAc,dried (MgSO₄) and concentrated in vacuo to yield a brown gummy oil. Thecrude product was combined with another batch (1.06 g, 12.3 mmol) ofsimilar crude material and partially purified by silica gelchromatography, eluting with CH₃ OH (5% to 60%)--CH₂ Cl₂ (with 1 to 2%HOAc). The product was taken in 3N NaOH and washed with Et₂ O. Theaqueous layer was acidified to pH ca. 2 by addition of 6N HCl, saturatedwith Na₂ SO₄, and extracted repeatedly with EtOAc. The combined organiclayer was dried (MgSO₄), and concentrated in vacuo to afford Compound330a (2.5 g, 52% overall yield) as a brown oil.

(b) Compound 330b ##STR737##

Compounds 330a and 54 were reacted by a procedure analogous to that ofExample 262f to give the title Compound 330b.

m.p. 119°-122° C.; [α]_(D) =-3.5° (c=0.2, CH₃ OH)

Analysis calculated for: C₃₀ H₄₃ N₃ O₇ . 0.45 H₂ O C, 63.68; H, 7.82; N,7.43 Found: C, 63.63; H, 7.79; N, 7.48

EXAMPLE 331 Preparation of[1S-(1R*,2S*,3R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[carbamicacid], 3-tetrahydrofuranyl 1,1-dimethylethyl ester (Compound 331c)

(a) Compound 331a ##STR738##

To a solution of (S)-(+)-3-hydroxytetrahydrofuran (441 mg, 5.0 mmol) in15 mL of CH₂ Cl₂ -pyridine (5:1) cooled at 0° C. was added a solution ofpara-nitrophenylchloroformate (1.0 g, 5.0 mmol) in 12.5 mL of CH₂ Cl₂.The reaction was stirred at 0° C. for 1.0 h, then at RT overnight. Thereaction mixture was diluted with EtOAc and the organic layer was washedwith sat. aq. NaHCO₃ and brine, and dried (Na₂ SO₄). Flashchromatography (hexane-EtOAc: 10:1 to 2:1) on silica gel afforded 1.25 g(99%) of Compound 331a as a colorless liquid.

(b) Compound 331b ##STR739##

To a solution of Compound 48 (200 mg, 0.340 mmol) in 0.25 mL DMF wasadded i-Pr₂ NEt (220 mg; 1.7 mmol), followed by Compound 331a (112 mg,0.442 mmol) in DMF (0.3 mL). After stirring overnight at RT, thereaction was concentrated in vacuo and diluted with EtOAc. After washingwith aq. 1N NaOH, sat. aq. NaHCO₃ and brine, the organic phase was dried(MgSO₄) and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel, eluting with a gradient from 0.5-5%MeOH/CH₂ Cl₂ to afford 0.2 g (83%) of a yellow foam.

Mass Spec. (Fab): (M+H)⁺ 702⁺.

(c) Compound 331c ##STR740##

To Compound 331b (200 mg, 0.284 mmol) in THF (2 mL) was added solidn-Bu₄ NF.nH₂ O (223 mg, 0.854 mmol) and the mixture stirred at 50° C.for 5 h. The reaction was concentrated in vacuo, the residue dissolvedin EtOAc, and washed with sat. aq. NaHCO₃ and brine. The organic phasewas dried (MgSO₄) and concentrated in vacuo to give a solid which waspurified by flash chromatography on silica gel, eluting with a gradientfrom 98.5:1.5:0.15 to 92.5:7.5:0.75 CH₂ Cl₂ :MeOH:NH₄ OH, to afford thetitle Compound 331c (102 mg, 64%) as a white solid.

m.p. 200°-202° C.; [α]_(D) =-14.5° (c=0.2, CH₃ OH)

Mass Spec. (CI): (M+H)⁺ 558.

Analysis calculated for: C₃₀ H₄₃ N₃ O₇ . 1.70 H₂ O C, 61.08; H, 7.96; N,7.12. Found: C, 61.10; H, 7.45; N, 7.10.

EXAMPLE 332 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-oxo-2-(1-tetrahydropyranyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 332c)

(a) Compound 332a ##STR741##

Bromoacetyl bromide (0.87 g, 10 mmol) was added dropwise to a stirringsolution of piperidine (2.03 ml, 20.60 mmol) in anhydrous Et₂ O (21 ml)at 0° C. After 20 min, the reaction was filtered, and the solid washedwith Et₂ O. The filtrate was concentrated in vacuo and the crudematerial chromatographed on a CC₇ column, eluting with EtOAc, to afford1.27 g (62%) of Compound 332a as a yellow oil.

(b) compound 332b ##STR742##

Compounds 175c and 332a were reacted by a procedure analogous to that ofExample 226a to give Compound 332b.

(c) Compound 332c ##STR743##

Compounds 16b and 332b were reacted by a procedure analogous to that ofExample 226b to give the title Compound 332c (colorless solid).

m.p. 116°-118° C.; [α]_(D) =-6.0° (c, 0.10 MeOH).

Mass spec.: (M+H) 685.

Analysis calc. for C₃₇ H₅₆ N₄ O₈ . 0.53 H₂ O. C, 64.00; H, 8.28; N,8.07; Found: C, 64.05; H, 8.43; N, 8.02.

EXAMPLE 333 Preparation of[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-Hydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 2-hydroxy-1,1-dimethylethyl ester (Compound 333d)

(a) Compound 333a ##STR744##

To a solution of Compound 298c (380 mg, 0.93 mmol) in DMF (0.5 mL) wasadded Compound 44a (276 mg, 0.93 mmol) and the solution heated at. 100°C. for 4 h. The reaction mixture was cooled to RT and DMF removed invacuo. Purification by silica gel chromatography, eluting with astepwise gradient from 99.5:0.5:0.05 to 90:10:1 CH₂ Cl₂ :CH₃ OH:aq.NH₄OH afforded Compound 333a (367 mg, 55% yield) as a white residue.

Mass Spec: (M+H)⁺ =708.

(b) Compound 333b ##STR745##

To a solution of Compound 333a (365 mg, 0.52 mmol) in EtOH (14 mL) andEtOAc (3.5 mL) was added 20% Pd(OH)₂ /C (110 mg total added in threeportions over the reaction) and the slurry stirred under a H₂ atmosphereovernight. Filtration, evaporation, and trituration of the resultingsolid gave Compound 333b (230 mg, 77% yield) as a white solid.

Mass Spec: (M+H)⁺ =574

(c) Compound 333c ##STR746##

To a solution of Compound 333b (127 mg, 0.22 mmol) in DMF (0.25 mL) wasadded a solution of Compound 262e (35.6 mg, 0.243 mmol) in 0.25 mL DMF,followed by BOP reagent (107.5 mg, 0.243 mmol) and N-methylmorpholine(53.45 μL) and the reaction stirred for 36 h. The DMF was evaporated invacuo and the residue dissolved in EtOAc which was washed with satd.NaHCO₃ and brine and dried (MgSO₄). Silica gel chromatography elutingwith a stepwise gradient from 98:2:0.2 to 90:10:1 CH₂ Cl₂ :CH₃ OH:aq.NH₄OH afforded Compound 333c (105 mg, 67% yield) as a solid.

Mass Spec: (M+H)⁺ =702

(d) Compound 333d ##STR747##

To a solution of Compound 333c (103 mg, 0.146 mmol) in THF (1.5 mL) wasadded H₂ O (0.5 mL) and HOAc (0.5 mL) and the reaction mixture stirredat RT for 2 d. Evaporation to dryness, azeotroping with H₂ O andpurification by silica gel chromatography eluting with a stepwisegradient from 98:2:0.2 to 90:10:1 CH₂ Cl₂ :CH₃ OH:aq.NH₄ OH afforded thetitle Compound 333d (74 mg, 86% yield) as a white solid.

m.p. 185°-188° C.; [α]_(D) =+19.5° (c=0.2, CH₃ OH)

Mass spec. (CI): (M+H)⁺ 588⁺.

Analysis calc. for: C₃₂ H₄₉ N₃ O₇ . 0.75 H₂ O C, 63.93; H, 8.47; N, 6.99Found: C, 63.93; H, 8.32; N, 7.11

EXAMPLE 334 Preparation of[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-Hydroxy-3,3-dimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 334) ##STR748##

To an ice cooled solution of 73 mg (0.55 mmol) of(R)-3,3-dimethyl-2-hydroxybutanoic acid (Ito et al., Synthesis, 137(1993)), 244 mg (0.55 mmol) of Compound 54, 111 mg (0.83 mmol) of HOBTand 121 μl (1.1 mmol) of N-methylmorpholine was added 105 mg (0.55 mmol)of EDCI as a solid. Stirring was continued with cooling for 1 h, then atRT overnight. The resulting solution was then added with stirring to anice-sat. NaHCO₃ mixture. The resulting precipitate was filtered andwashed with H₂ O. The crude product was taken into CH₂ Cl₂, dried(MgSO₄), and the solution placed on a 50 cc column of silica gel.Elution with CHCl₃ :MeOH:NH₄ OH (95:5:0.5) afforded impure product. Thismaterial was recrystallized from CH₂ Cl₂ and then rechromatographed on a100 cc column of silica gel. A gradient elution with CHCl₃ :MeOH:NH₄ OH(95:5:0.1 to 0.5) afforded 20 mg of Compound 334 as a white powder.

m.p. 175°-176° C.; [α]_(D) =+1.1° (c 0.08, MeOH).

Mass. Spec.: (M+H)⁺ 558⁺

Analysis Calc. for C₃₁ H₄₇ N₃ O₆ . 0.25 H₂ O: C, 66.23; N, 8.52; N,7.47. Found: C, 66.23, H, 8.46; N, 7.39.

EXAMPLE 335 Preparation of[1S-[1R*,2S*[2S*,3R*(R*)]]]-[3-[[3-[(2-Hydroxy-3,3-dimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 335) ##STR749##

Compound 335 (white solid) was prepared from(S)-3,3-dimethyl-2-hydroxybutanoic acid and Compound 54 by a procedureanalogous to that of Example 334.

m.p.: 92°-96° C.; [α]_(D) =-2.7° (c 0.81, MeOH).

Mass. Spec.: (M+H)⁺ 558⁺

Analysis Calc. for C₃₁ H₄₇ N₃ O₆ . 1.0 H₂ O: C, 64.60; N, 8.58; N, 7.29.Found: C, 64.60; H, 8.57; N, 7.02.

EXAMPLE 336 Preparation ofN,N'-[Iminobis[(1S,2R)-2-Hydroxy-1-(Phenylmethyl)-3,1-propanediyl]]bis-[1-hydroxy-2,2-dimethylcyclopentanecarboxamide],isomer A (Compound 336b)

(a) Compound 336a ##STR750##

A solution of Compound 321d (115 mg; 0.197 mmol) in 3 ml of HClsaturated EtOAc was stirred 1 h at 0° C. The volatiles were removed invacuo to afford 109 mg (99%) of Compound 336a as an off-white solid.

¹ H NMR (CD₃ OD): δ 0.82 (s, 3H), 0.94 (s, 3H), 1.65 (m, 5H), 2.05 (m,1H), 2.80 (dd, J=10.5, 13.5 Hz, 1H), 2.91 (dd, J=8.5, 14.5 Hz, 1H), 3.04(m, 3H), 3.22 (m, 3H), 3.70 (m, 1H), 3.90 (m, 1H), 4.03 (m, 1H), 4.25(m, 1H), 7.33 (m, 10H).

(b) Compound 336b ##STR751##

BOP-reagent (89 mg; 0.200 mmol) was added in one portion to a solutionof Compound 336a (105 mg; 0.189 mmol), Compound 321c (30 mg; 0.190) andN-methylmorpholine (65 ml; 0.580 mol) at 0° C. in 0.5 ml of DMF. Thereaction mixture was allowed to warm to RT and stir 18 h. After dilutingwith EtOAc, the organic phase was washed with H₂ O, saturated NaHCO₃solution and brine. After drying (Na₂ SO₄), the solvent was removed invacuo. The residue was preabsorbed on celite and chromatographed on a2.5×15 cm silica gel column eluting with CH₂ Cl₂ ; 1% MeOH/CH₂ Cl₂ ; 2%MeOH/CH₂ Cl₂ ; 2.5% MeOH/CH₂ Cl₂ ; then 3-5% MeOH/CH₂ Cl₂ +0.3-0.5% NH₄OH in 0.25% and 0.025% increments respectively to afford 14.4 mg (12%)of Compound 336b (white solid) as a single symmetrical isomer ofundetermined absolute configuration.

m.p. 135°-145° C.; R_(f) =0.25, CH₂ Cl₂ :MeOH:NH₄ OH, 90:9:1 (UV and PMAdetection); [α]_(D) =+28.2° (c 0.38, MeOH).

Mass Spec.: M+H=624.

EXAMPLE 337 Preparation ofN,N'-[Iminobis[(1S,2R)-2-Hydroxy-1-(Phenylmethyl)-3,1-propanediyl]]bis-[1-hydroxy-2,2-dimethylcyclopentanecarboxamide],isomer B (Compound 337) ##STR752##

Compound 337 was isolated as the more polar isomer from the reactiondescribed in Example 336. Recrystallization from ether/hexane gave 18 mg(15%) of a white solid.

m.p. 109°-112° C.; R_(f) =0.19, CH₂ Cl₂ :MeOH:NH₄ OH, 90:9:1 (UV and PMAdetection); [α]₃₆₅ =+25.7° (c 0.33, MeOH).

Mass Spec.: M+H=624.

Analysis Calc. for C₃₆ H₅₃ N₃ O₆ . 1.35 H₂ O: C, 66.71; N, 8.66; N,6.48. Found: C, 66.52, H, 8.52; N, 6.67.

EXAMPLE 338 Preparation of[1S-(1R*,2S*),(R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[carbamicacid], bis(3-tetrahydrofuranyl)ester (Compound 338b)

(a) Compound 338a ##STR753##

Compound 32 was reacted with 3 eq. of Compound 331a and 10 eq. of iPr₂NEt by a procedure analogous to that of Example 149e (DMF was used inplace of CH₃ CN) to give Compound 338a.

(b) Example 338b ##STR754##

Compound 338a was converted to the title Compound 338b (white solid) bya procedure analogous to that of Example 2.

m.p. 230°-231° C.; [α]_(D) =-23.5° (c 0.2, HOAc).

Mass Spec. (FAB): 572⁺ (M+H)⁺.

Analysis Calc. for C₃₀ H₄₁ N₃ O₈ : C, 63.03; H, 7.23; N, 7.35. Found: C,63.19; H, 7.33; N, 7.04.

EXAMPLE 339 Preparation of[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamicacid, (2-furo[2,3-c]pyridinyl) methyl ester (Compound 339f)

(a) Compound 339a ##STR755##

Compound 339a was prepared as described in Shiotani et al. , J. Heter.Chem., 19, 1207 (1982).

(b) Compound 339b ##STR756##

Compound 339b was prepared from Compound 39a as described in Shiotani etal., J. Heter. Chem., 24, 373 (1987).

(c) Compound 339c ##STR757##

To a solution of Compound 339b (0.66 g, 4.49 mmol) in 50 mL of 3:3:4THF-EtOH-CHCl₃ cooled to 0° C. was added NaBH₄ (0.298 g, 7.86 mmol) inportions. After addition was complete, the mixture was stirred at 0° C.for 30 min, diluted with H₂ O and extracted with CH₂ Cl₂. The combinedextracts were dried (MgSO₄) and concentrated. The crude residue wasflash chromatographed on silica gel eluting with a stepwise gradient of25% to 100% EtOAc-hexane to afford Compound 339c (0.555 g, 83%) as awhite solid.

(d) Compound 339d ##STR758##

To a solution of Compound 339c (0.298 g, 2 mmol) in 15 mL of CH₂ Cl₂cooled to 0° C. was added 1 mL of pyridine followed byp-nitrophenylchloroformate (0.403 g, 2 mmol) as a solid. The reactionmixture was stirred for 16 h at RT, diluted with EtOAc and washed withsat. NaHCO₃ and brine. The organic phase was dried (MgSO₄) andconcentrated to obtain Compound 339d (0.6 g, 95%; crude yield)containing traces of p-nitrophenylchloroformate and p-nitrophenol.

(e) Compound 339e ##STR759##

Compound 339d (0.6 g; 1.91 mmol) in 5 mL of dioxane was added to asolution of L-tert-leucine (0.25 g; 1.91 mmol) in 1.92 mL of 1N NaOH atRT followed by the addition of Et₃ N (293 μL; 2.1 mmol). After 24 h atRT, the reaction mixture was diluted with 10% KHSO₄ and extracted withEtOAc. The aqueous phase was brought to pH 3.5 with 2N NaOH andextracted with EtOAc. The organic extracts were washed with brine, dried(MgSO₄) and concentrated to afford 0.5 g (85%) of Compound 339e as anoff-white solid.

(f) Compound 339f ##STR760##

To a 0° C. solution of Compound 339e (0.173 g; 0.56 mmol) in 3 mL of CH₂Cl₂ was added HOBT (0.115 g; 0.84 mmol) followed by EDCI (0.114 g; 0.59mmol). After 30 min, Compound 54 (0.25 g; 0.56 mmol) was added followedby 0.5 mL of DMF. The reaction mixture was stirred at 0° C. for 30 minand at RT for 16 h, at which time it was diluted with CH₂ Cl₂, andwashed with H₂ O, sat. aq. NaHCO₃ and brine. The organic extracts weredried (MgSO₄), concentrated, and the resulting residue purified by flashchromatography on silica gel, eluting with a gradient of 96.7:3:0.3 to89:10:1 CH₂ Cl₂ :MeOH:NH₄ OH, to afford 0.135 g (33%) of the titleCompound 339f as an off-white solid.

m.p. 95°-105° C.; [α]_(D) =-19.4° (c=0.2, CH₃ OH).

Mass. Spec. (FAB) (M+H)⁺ =732

Analysis calc. for C₄₀ H₅₃ N₅ O₈.1.39 H₂ O: C, 63.42; H, 7.43; N, 9.25Found: C, 63.33; H, 7.23; N, 9.34.

EXAMPLE 340 Preparation of[1S*,2R*(2R*,3S*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-methoxycarbonyl)-3-methyl-D-valinamide (Compound 340) ##STR761##

(D)-t-Leucine and Compound 54 were converted to the title Compound 340by the two-step procedure described in Example 246.

m.p. 135°-143° C.; [α]_(D) =+13.4° (c=0.2, CH₃ OH).

Mass Spec. (FAB) (M+H)⁺ =615

Analysis calc. for C₄₀ H₅₃ N₅ O₈.1.39 H₂ O: C, 61.95; H, 8.31; N, 8.76Found: C, 61.95; H, 8.12; N, 8.93.

EXAMPLE 341 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[[4-[2-(4-morpholinyl)-2-oxoethoxy]phenyl]methyl]propyl]-N²-(2-methoxycarbonyl)-3-methyl-L-valinamide (Compound 341e)

(a) Compound 341a ##STR762##

Compound 226a was converted to Compound 341a by a two-step procedureanalogous to that used for the conversion of Compound 282a to Compound282c.

(b) Compound 341b ##STR763##

Compound 341a was converted to Compound 341b by a procedure analogous tothat of Example 122 except that carbobenzyloxy chloride was used.

(c) Compound 341c ##STR764##

Compounds 341b and 1b(i) were converted to Compound 341c by a two-stepprocedure analogous to that used for the conversion of Compound 282d toCompound 282f.

(d) Compound 341d ##STR765##

Compound 341c was converted to Compound 341d by a procedure analogous tothat of Example 19.

(e) Compound 341e ##STR766##

Compounds 341d and 246a were reacted by a procedure analogous to that ofExample 246b to give the title Compound 341e (white solid).

m.p. 128°-130° C.; [α]_(D) =-12° (c=0.07, MeOH).

Mass spec.: 758⁺ (M+H)⁺.

Analysis calc. for C₃₉ H₅₉ N₅ O₁₀ . 0.9 H₂ O: C, 60.51; H, 7.92; N,9.05; Found: C, 60.79; H, 8.01; N, 8.65.

EXAMPLE 342 Preparation of[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(methylamino)carbonyl]-N² -3-dimethyl-L-valinamide (Compound 342f )

(a) Compound 342a ##STR767##

Compound 88a was converted to Compound 342a by a procedure analogous tothat of Example 66a (except that DMF was used as solvent instead ofTHF).

(b) Compound 342b ##STR768##

Compound 342a was converted to Compound 342b by a procedure analogous tothat of Example 70c except that the reaction was not acidified beforeevaporation.

(c) Compound 342c ##STR769##

To a 0° C. solution of Compound 48 (200 mg; 0.34 mmol) and Compound 342b(102 mg; 0.35 mmol) in anhydrous DMF (0.68 mL) were successively addedBOP reagent (0.154 g; 0.350 mmol) and N-methyl morpholine (0.188 mL;1.71 mmol). The solution was allowed to warm to RT and stirred for 36 h.Volatiles were removed in vacuo and the residue was partitioned betweensaturated aqueous NaHCO₃ and EtOAc. The combined organic extracts werewashed with brine, dried (Na₂ SO₄), and concentrated in vacuo to give aviscous oil, which was chromatographed on silica gel using a gradientfrom 10% EtOAc-hexane to 50% EtOAc-hexane to furnish Compound 342c (233mg; 81%) as a white solid.

(d) Compound 342d ##STR770##

Compound 342c was converted to Compound 342d (white solid) by aprocedure analogous to that of Example 19.

(e) Compound 342e ##STR771##

Compound 342d and methyl isocyanate were reacted by a procedureanalogous to that of Example 46 to give Compound 342e (colorless oil).

(f) Compound 342f ##STR772##

Compound 342e was converted to the title Compound 342f (white solid) bya procedure analogous to that of Example 21.

m.p. 87°-90° C.

Mass Spec. (FAB): (M+H)=628

EXAMPLE 343 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-(2-oxo-3-oxazolidinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 343c)

(a) Compound 343a ##STR773##

Diethanolamine was converted to Compound 343a by a procedure analogousto that of Example 315a.

(b) Compound 343b ##STR774##

Compounds 175c and 343a were reacted by a procedure analogous to that ofExample 282a to give Compound 343b.

(c) Compound 343c ##STR775##

Compounds 16b and 343b were reacted by a procedure analogous to that ofExample 226b (except that the reaction was run in MeOH at 60° C.) toafford the title Compound 343c (colorless solid).

m.p. 130.5°-133.5° C.; [α]_(D) =-3.1° (c 0.27, MeOH).

Mass Spec.: (FAB): 673 (M+H).

Anal. Calc. for C₃₅ H₅₂ N₄ O₉ . 0.25 H₂ O C, 62.07; H, 7.81; N, 8.27Found: C, 62.04; H, 7.84; N, 8.29.

EXAMPLE 344 Preparation of[2R-[R*(R*,S*)]]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[2-hydroxy-2,3,3-trimethylbutaneamide](Compound 344) ##STR776##

BOP reagent (308 mg, 0.7 mmol) was added to a stirred mixture ofCompound 74 (0.15 g, 0.33 mmol), Compound 262e (0.102 g, 0.7 mmol) andN-methylmorpholine (0.254 mL, 2.32 mmol) in 0.75 mL dry DMF. The mixturewas stirred at RT for 14 h, concentrated and the residue partitionedbetween EtOAc and sat. NaHCO₃. The organic phase was dried (MgSO₄),concentrated, and the residue purified by flash chromatography (silicagel/CH₂ Cl₂ stepwise to 95:5:0.5 CH₂ Cl₂ --MeOH-aq NH₄ OH) followed bypreparative HPLC (column: Polymer Labs. PLRP-S 100 Å 10 μm 25×300 mm;eluent: 1:1 A:B, eluent A=H₂ O--CH₃ CN--NH₄ OH 90:10:0.2, eluent B=H₂O--CH₃ CN--NH₄ OH 10:90:0.2; UV 254 nm) to afford 100 mg (50%) of thetitle Compound 344 as a white solid.

m.p. 159°-160° C.; [α]_(D) +43.8° (c 0.48, MeOH).

Mass. Spec.: 600 (M+H)⁺.

Analysis calc. for C₃₄ H₅₃ N₃ O₆.0.59 H₂ O: C, 66.90; H, 8.95; N, 6.88.Found: C, 66.89; H, 8.90; N, 6.89.

EXAMPLE 345 Preparation of[S-(1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamicacid, (4-phenyl-2-oxazolyl)methyl ester (Compound 345b)

(a) Compound 345a ##STR777##

A solution of 4-phenyloxazole (Whitney, J. Org. Chem., 55, 929-935(1990)) (2.15 g; 14.8 mmol) and 2,2,4,4-tetramethylpiperidine (250 μl;1.48 mmol) in 30 ml of distilled THF at -78° C. was added 1.3M s-BuLi incyclohexane (13.7 ml). The mixture was stirred for 30 min at -78° C. andthen warmed to 0° C. Formaldehyde gas (from paraformaldehyde) wasbubbled through the mixture for 5 min and it was allowed to warm to RTand stir overnight. The reaction was quenched with 1N HCl and extractedwith CH₂ Cl₂. The extracts were washed with brine and dried (Na₂ SO₄).Evaporation and purification on a silica gel column eluting withEtOAc/hexane (1:3) and EtOAc/hexane (1:1) gave 1.75 g (68%) Compound345a.

(b) Compound 345b ##STR778##

Compound 345a was converted to its p-nitrophenyl carbonate which wasreacted with tert-leucine and the resulting product coupled withCompound 54 by a three-step procedure analogous to that used for Example257a through 257c to give the title Compound 345b (colorless solid).

m.p. 178°-184° C. (dec).; [α]_(D) =-11° (c=0.25, MeOH).

Analysis calcd. for: C₄₂ H₅₅ N₅ O₈ . 0.5 H₂ O: C, 65.73; H, 7.36; N,9.12 Found: C, 65.73; H, 7.30; N, 9.12

Mass Spec. (FAB): (M+H)⁺ =758⁺.

EXAMPLE 346 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[4-[4-(Carboxymethoxy)phenyl)-3-[[3-[[1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl)carbamicacid, 1,1-dimethylethyl ester (Compound 346c)

(a) Compound 346a ##STR779##

To a 0° C. solution of Compound 175c (0.080 g; 0.286 mmol) in DMF (0.60ml) was added a solution of NaN(TMS)₂ in THF (0.30 ml of a 1.0Msolution; 0.30 mmol). The solution was stirred at 0° C. for 1 h, thenethyl bromoacetate in DMF (0.30 mL of a 1.0M solution; 0.30 mmol) wasadded dropwise, followed by Bu₄ NI (0.011 g; 0.029 mmol). The solutionwas allowed to warm to RT and stirred for 18 h. Volatiles were removedin vacuo, and the residue was partitioned between H₂ O and EtOAc. Thecombined organic extracts were washed with H₂ O, dried (Na₂ SO₄) andconcentrated in vacuo to give, after chromatography on silica gel (50mL) using a gradient from 10:1 to 1:2 hexane:EtOAc as eluent, Compound346a (0.100 g; 95%) as a white solid.

(b) Compound 346b ##STR780##

Compounds 346a and 16b were reacted by a procedure analogous to that ofExample 226b to give Compound 346b.

Mass Spec. (CI): (M+H)⁺ =646

(c) Compound 346c ##STR781##

Compound 346b was converted to the title Compound 346c (white solid) bya procedure analogous to that of Example 70c (THF was used instead ofdioxane).

m.p.=182°-187° C. (dec)

Mass Spec. (FAB): (M+H)⁺ =618.

EXAMPLE 347 Preparation of[S-(1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamicacid, (5-phenyl-2-oxazolyl)methyl ester (Compound 347b)

(a) Compound 347a ##STR782##

5-Phenyloxazole-2-carboxylic acid ethyl ester (Saito, J. Pharm. Soc.Japan, 76, 305 (1956)) was converted to Compound 347a by a procedureanalogous to that of Example 281a (except that the reaction was run at0° C. to RT).

(b) Compound 347b ##STR783##

Compound 347a was converted to its p-nitrophenyl carbonate which wasreacted with tert-leucine and the resulting product coupled withCompound 54 by a three-step procedure analogous to that used for Example257a through 257c to give the title Compound 347b (colorless solid).

m.p. 168°-174° C. (dec).; [α]_(D) =-12.5° (c=0.25, MeOH).

Mass Spec. (FAB): (M+H)⁺ =758⁺

Analysis calcd. for: C₄₂ H₅₅ N₅ O₈ . 0.68 H₂ O: C, 65.50; H, 7.38; N,9.09 Found: C, 65.46; H, 7.29; N, 9.13.

EXAMPLE 348 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[2-(phenylmethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 348d)

(a) Compound 348a ##STR784##

D,L-o-Tyrosine was resolved into the (L) enantiomer, Compound 348a, bythe procedure described in Can. J. Biochem., 49, 877 (1971).

(b) Compound 348b ##STR785##

Compound 348a was converted to Compound 348b by a three-step procedureanalogous to that used for the conversion of Compound 28b to Compound28e.

(c) Compound 348c ##STR786##

Compound 348b was converted into Compound 348c by procedures analogousto those used for the synthesis of Compound 1b(i).

(d) Compound 348d ##STR787##

Compounds 348c and 16b were reacted by a procedure analogous to that ofExample 226b to give the title Compound 348d (colorless solid).

m.p. 146°-152° C.; [α]_(D) =-4° (c 0.8, HOAc)

Mass Spec. (CI): (M+H)⁺ =650⁺

Analysis calcd. for: C₃₇ H₅₁ N₃ O₇ . 1.5 H₂ O: C, 65.65; H, 8.04; N,6.41 Found: C, 65.49 H, 7.72; N, 6.66.

EXAMPLE 349 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-1,1-Dimethylethoxy)-carbonyl]amino]-2-hydroxy-4-(2-methoxyphenyl)butyl]-amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 349c)

(a) Compound 349a ##STR788##

Compound 348c was converted to Compound 349a by a procedure analogous tothat of Example 175c.

(b) Compound 349b ##STR789##

A solution of Compound 349a (70 mg, 0.25 mmol) in 0.5 ml of dry DMF wascooled to 0° C. and 250 μl of a 1M solution of sodiumbis(trimethylsilyl)amide in THF (46 mg, 0.25 mmol) was added. Afterstirring for 15 min, 10 eq. of CH₃ I (0.15 ml, 2.5 mmol) was added andthe resulting mixture was stirred at 0° C. for 1 h and then allowed towarm to RT and stir overnight. The DMF was evaporated and the crudeproduct purified on a 20 ml silica gel column eluting with 15%EtOAc/hexane yielding 68 mg (93%) of Compound 349b.

(c) Compound 349c ##STR790##

Compounds 349b and 16b were reacted by a procedure analogous to that ofExample 226b to give the title Compound 349c (colorless solid).

m.p. 136°-140° C.; [α]_(D) =-3.5° (c 0.5, HOAc)

Mass Spec. (CI): (M+H)⁺ =574⁺

Analysis calcd. for: C₃₁ H₄₇ N₃ O₇ . 1.45 H₂ O: C, 62.07; H, 8.38; N,7.01 Found: C, 61.92; H, 8.08; N, 7.16.

EXAMPLE 350 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(2-hydroxyphenyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 350) ##STR791##

Compound 348d was converted to the title Compound 350 (colorless solid)using conditions analogous to those of Example 43.

m.p. 156°-160° C.; [α]_(D) =-5.2° (c 0.5, HOAc)

Mass Spec. (CI): (M+H)⁺ =560⁺

Analysis calcd. for: C₃₀ H₄₅ N₃ O₇ . 1.18 H₂ O: C, 62.03; H, 8.22; N,7.23 Found: C, 61.95; H, 7.79; N, 7.31.

EXAMPLE 351 Preparation of[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamicacid, 2-(phenylmethoxy)ethyl ester (Compound 351) ##STR792##

2-Benzyloxyethanol was converted to its p-nitrophenyl carbonate whichwas reacted with tert-leucine and the resulting product coupled withCompound 54 by a three-step procedure analogous to that used for Example257a through 257c to give the title Compound 351 (white solid).

m.p. 99°-101° C.; [α]_(D) =-13° (c 0.11, MeOH).

Mass spec.: 735⁺ (M+H)⁺.

Analysis calc. for C₄₁ H₅₈ N₄ O₈ . 1.61 H₂ O: C, 64.46; H, 8.08; N,7.33; Found: C, 64.15; H, 7.83; N, 7.51.

EXAMPLE 352 Preparation of[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamicacid, (2-furo[2,3-b]pyridinyl)methyl ester (Compound 352h)

(a) Compound 352a ##STR793##

Compound 352a was prepared as described in Sliwa, Bull Soc. Chim. Fr.631 (1970).

(b) Compound 352b ##STR794##

Compound 352a was converted to Compound 352b by the procedure describedin Morita et al., J. Heter. Chem., 23, 1465 (1986).

(c) Compound 352c ##STR795##

Compound 352b was converted to Compound 352c by the procedure describedin Sliwa, Bull Soc. Chim. Fr. 646 (1970).

(d) Compound 352d ##STR796##

Compound 352c was converted to Compound 352d by the procedure describedin Morita et al., J. Heter. Chem., 23, 1465 (1986).

(e) Compound 352e ##STR797##

To a solution of Compound 352d (0.26 g, 1.769 mmol; ca. 75% pure) in 20mL of 3:3:4 THF-EtOH-CHCl₃ cooled to 0° C. was added NaBH₄ (0.117 g,3.095 mmol) in portions. After addition was complete, the mixture wasstirred at 0° C. for 30 min, diluted with H₂ O and extracted with CH₂Cl₂. The combined extracts were dried (MgSO₄) and concentrated. Thecrude residue was flash chromatographed on silica gel eluting with astepwise gradient of 25% to 100% EtOAc-hexane to afford Compound 352e(0.16 g, 80%) as a white solid.

(f) Compound 352f ##STR798##

To a solution of Compound 352e (0.160 g, 1.073 mmol) in 8 mL of CH₂ Cl₂cooled to 0° C. was added 0.5 mL of pyridine followed byp-nitrophenylchloroformate (0.216 g, 1.073 mmol) as a solid. Thereaction mixture was stirred for 20 h at RT, diluted with EtOAc andwashed with sat. NaHCO₃ and brine. The organic phase was dried (MgSO₄)and concentrated to obtain Compound 352f (0.336 g, crude yield)containing traces of p-nitrophenylchloroformate and p-nitrophenol.

(g) Compound 352g ##STR799##

Compound 352f (0.336 g; 1.07 mmol) in 5 mL of dioxane was added to asolution of L-tert-leucine (0.154 g; 1.177 mmol) in 1.17 mL of 1N NaOHat RT followed by the addition of Et₃ N (179 μL; 1.284 mmol). Afterstirring overnight at RT, the reaction mixture was diluted with 10%KHSO₄ and the pH adjusted to 2.0 with 1N NaOH. The mixture was extractedwith EtOAc and the combined extracts were washed with brine, dried(MgSO₄) and concentrated. Flash chromatography on silica gel of thecrude residue (CH₂ Cl₂ followed by a stepwise gradient from 2% to 10%MeOH/CH₂ Cl₂ +0.5% HOAc) afforded 0.23 g (ca. 80% pure) of Compound352g.

(h) Compound 352h ##STR800##

To a 0° C. solution of Compound 352g (0.15 g; 0.40 mmol based on 80%pure material) in 3 mL of CH₂ Cl₂ was added HOBT (0.092 g; 0.676 mmol)followed by EDCI (0.091 g; 0.474 mmol). After 30 min, Compound 54 (0.20g; 0.451 mmol) was added followed by 0.5 mL of DMF. The reaction mixturewas stirred at 0° C. for 30 min and at RT for 16 h, at which time it wasdiluted with EtOAc, and washed with H₂ O, sat. aq. NaHCO₃ and brine. Theorganic extracts were dried (MgSO₄), concentrated, and the resultingresidue purified by flash chromatography on silica gel, eluting with agradient of 98.9:1:0.1 to 90.1:9:0.9 CH₂ Cl₂ :MeOH:NH₄ OH, to afford0.238 g (72%) of the title Compound 352h as an off-white solid.

m.p. 99°-106° C.; [α]_(D) =-15.2° (c=0.2, CH₃ OH).

Mass Spec. (FAB) (M+H)⁺ =732

Analysis calc. for C₄₀ H₅₃ N₅ O₈ . 1.28 H₂ O: C, 63.64; H, 7.42; N, 9.28Found: C, 63.54; H, 7.37; N, 9.38.

EXAMPLE 353 Preparation of[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-Hydroxy-1-oxo-2-phenylpropyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethyl ethyl ester (Compound 353) ##STR801##

To a solution of Compound 54 (100 mg, 0.225 mmol) in DMF (0.4 ml) wasadded a solution of (R)-2-hydroxy-2-phenylpropionic acid (41 mg, 0.247mmol) in 0.3 ml DMF, followed by BOP reagent (109 mg, 0.247 mmol) andN-methylmorpholine (54 μl; 0.49 mmol) to afford 55 mg (41%) the titleCompound 353 using a procedure analogous to that of Example 262f.

m.p. 161°-163° C.; [α]_(D) =+2.5° (c 0.2, CH₃ OH)

Mass spectrum (Fab): (M+H)⁺ 592⁺.

Analysis Calc. for: C₃₄ H₄₅ N₃ O₆ . 0.51 H₂ O: C, 67.95; H, 7.72; N,6.99 Found: C, 67.92; H, 7.48; N, 7.02.

EXAMPLE 354 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[3,3-Dimethyl-2-[(methylamino)carbonyl]-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 354d)

(a) Compound 354a ##STR802##

2-tert-Butyl-diethylmalonate was saponified with KOH/EtOH to affordCompound 354a as described in Bajwa et al. J. Amer. Chem. Soc., 104,6385 (1982).

(b) Compound 354b ##STR803##

A solution of Compound 354a (1.0 g, 5.31 mmol) in 0.775 ml (10.62 mmol)of SOCl₂ was refluxed for 2 h. The excess SOCl₂ was removed in vacuo andthe residue was dissolved in 20 ml dry Et₂ O. Anhydrous CH₃ NH₂ wasbubbled into the reaction until no more precipitate formed. Theprecipitate was filtered off and the filtrate was concentrated to afford865 mg (81%) of Compound 354b.

(c) Compound 354c ##STR804##

Compound 354c was prepared from Compound 354b by a procedure analogousto that used for the preparation of Compound 354a.

(d) Compound 354d ##STR805##

Compound 354d (white solid) was prepared as a 1:1 mixture ofdiastereomers from Compounds 354c and 54 by a procedure analogous tothat of Example 334.

m.p. 117°-120° C. ("softening" at 114°-117° C.)

Mass Spec. (FAB), 599 (M+H⁺)

Analysis Calc. for: C₃₁ H₅₀ N₄ O₆ . 0.16 H₂ O: C, 65.87; H, 8.43; N,9.31 Found: C, 65.84; H, 8.55; N, 9.34.

EXAMPLE 355 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-hydroxy-2-(3-pyridinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, Isomer A (Compound 355f)

(a) Compound 355a ##STR806##

Pyridine 3-carboxaldehyde (4.0 g; 37.3 mmol) in THF (50 mL) was reactedwith vinyl magnesium bromide (41.0 mL of a 1.0M solution in THF; 41.0mmol), first at 0° C. then at RT for 24 h. The reaction mixture wascooled to 0° C. and aqueous NH₄ Cl (55 mL of a 1M solution) was slowlyadded, followed by EtOAc (200 mL). The resulting mixture was filteredthrough Celite and the aqueous layer extracted with EtOAc. The combinedorganic extracts were dried (Na₂ SO₄) and concentrated in vacuo to givean oil, which was purified by flash chromatography (500 mL SiO₂ ;stepwise gradient from 1:1 to 1:5 hexanes:EtOAc) to give Compound 355a(3.89 g; 77%) as a pale yellow oil.

(b) Compound 355b ##STR807##

To a 0° C. solution of Compound 355a (0.40 g; 2.96 mmol) in anhydrousDMF (3.0 mL) were successively added tert-butyldimethylsilyl chloride(0.535 g; 3.55 mmol), Et₃ N (0.467 g; 4.62 mmol) and DMAP (0.036 g;0.296 mmol). The mixture was allowed to warm to RT and stirred for 24 h.Volatiles were removed in vacuo and the residue was partitioned betweenaqueous NaHCO₃ (20 mL of a 50% saturated solution) and EtOAc (20 mL).The aqueous layer was extracted with EtOAc and the combined organicextracts were washed with H₂ O, dried, and concentrated in vacuo to givean oil. Flash chromatography (SiO₂ ; 100 mL) using as eluent 10:1hexane:EtOAc furnished Compound 355b (0.744; 100%) as a pale yellow oil.

(c) Compound 355c ##STR808##

A stream of O₃ was bubbled into a -78° C. solution of Compound 355b(0.650 g; 2.61 mmol) in CH₂ Cl₂ (10.0 mL) for 15 min until the solutionwas faintly blue. After stirring for a further 30 min at -78° C., N₂ wasbubbled into the solution for 15 min to discharge the blue color.DIBAL-H (10.4 mL of a 1.0M solution in hexane; 10.4 mmol) was addeddropwise over 5 min, followed by 10 mL of dry hexane. The solution wasstirred at -78° C. for 1 h, then at -20° C. for 2 h. The solution wasthen recooled to -78° C. and MeOH (3.0 mL) was added dropwise. Thesolution was allowed to warm to RT and brine (5.0 mL), Et₂ O (100 mL)and MgSO₄ (15 g) were added. The mixture was stirred for 2 h, filtered,and concentrated in vacuo to give a yellow oil, which was flashchromatographed (SiO₂ ; 100 mL) using a stepwise gradient from 1:1 to1:4 hexane:EtOAc to give Compound 355c (0.234g; 35%) as a slightlyyellow oil.

(d) Compound 355d ##STR809##

Compound 355c (0.331 g; 1.31 mmol) and Compound 175c (0.183 g; 0.655mmol) were reacted with DEAD (0.228 g; 1.31 mmol) and Ph₃ P (0.343 g;1.31 mmol) in THF for 24 h at RT. The solution was concentrated in vacuoand adsorbed onto Celite. Flash chromatography (100 mL SiO₂) using agradient from 95:5 to 1:1 hexane:EtOAc gave Compound 355d (0.301 g;contaminated with 1,2-dicarbethoxyhydrazine; only one of two possiblediastereomers was isolated) as a pale yellow viscous oil.

(e) Compound 355e ##STR810##

Compound 355d (0.301 g) was dissolved in anhydrous THF and n-Bu₄ NF.H₂ O(0.204 g; 0.779 mmol) was added at RT. The yellow solution was stirredfor 1.5 h. Volatiles were removed in vacuo and the residue was purifiedby flash chromatography (SiO₂, 100 mL) using a gradient from 1:1 to 1:10hexane:EtOAc to give Compound 355e (0.096 g; 37% for 2 steps) as a whitesolid.

(f) Compound 355f ##STR811##

Compound 355e (0.030 g; 0.075 mmol) and Compound 16b (0.025 g; 0.090mmol) were heated in MeOH (0.20 mL) at 60° C. for 4 h. Volatiles wereremoved in vacuo and the residue was purified by flash chromatography onSiO₂ (100 mL) using as eluent a stepwise gradient from 99:1:0.1 to92:8:0.8 CH₂ Cl₂ :MeOH:NH₄ OH to afford a white solid (0.026 g, 52%).This material was further purified by preparative HPLC (Polymer LabsPLRP-S column, 25×300 mm, 10 μm particle size, stepwise gradient from70:30 to 40:60 A:B; A=90:10:0.2 H₂ O: MeCN: NH₄ OH, B=90:10:0.2 MeCN:H₂O:NH₄ OH) and then lyophilized from dioxane-H₂ O to give the titleCompound 355f (0.021 g; 41%) as a white solid (single diastereomer ofundetermined configuration).

m.p.=68°-72° C. (dec.); [α]_(D) =-4.0° (c=0.10, MeOH)

Mass Spec. (FAB): (M+H)⁺ =681.

EXAMPLE 356 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(2,4-Dihydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A (Compound 356b)

(a) Compound 356a ##STR812##

A solution of CH₃ MgCl (3M in THF, 14.32 mL, 43 mmol) was added to asolution of dihydro-4,4-dimethyl-2,3-furandione (5 g, 39 mmol) in 30 mLTHF at -78° C. The mixture was allowed to warm to RT, diluted with Et₂ Oand dilute HCl was added. The organic layer was washed with sat. NaHCO₃,dried (MgSO₄) and concentrated to afford 3.5 g of a colorless oil. Thismaterial was dissolved in 50 mL THF, and a solution of LiOH (583.4 mg,24.3 mmol) in 25 mL water was added and the mixture was refluxed for 24h. The mixture was concentrated, the residue dissolved in 30 mL water,washed with Et₂ O, and the aqueous phase lyophilized to afford 3.0 g ofa pale solid. This solid (1.0 g) was dissolved in 5 mL water which wasacidified with 10% HCl, extracted with EtOAc, and the organic phasedried (MgSO₄), concentrated, and the residue purified by flashchromatography (silica gel/hexane-EtOAc 1:1) to afford 0.815 g ofCompound 356a as a colorless oil.

(b) Compound 356b ##STR813##

A mixture of Compound 54 (200 mg, 0.45 mmol) and Compound 356a (129.8mg, 0.90 mmol) in 1 mL dry DMF was heated at 100° C. for 14 h and 145°C. for 2 h, concentrated, and the residue purified by flashchromatography to afford a ca. 1:1 mixture of the two diastereomeric (at*) products. This material was subjected to preparative TLC (0.5 mmsilica gel plates/CH₂ Cl₂ --MeOH--NH₄ OH 9:1:0.1, developed twice) toafford, as the faster moving isomer, the title Compound 356b (11 mg,4.1%) as a white solid.

m.p. 73°-75° C.; [α]_(D) +8° (c=0.15, MeOH); R_(f) (SiO₂)=0.23 (CH₂ Cl₂--MeOH--NH₄ OH 8:2:0.2).

Mass Spec.: 588 (M+H)⁺.

EXAMPLE 357 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(2,4-Dihydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer B (Compound 357) ##STR814##

Compound 357 (white solid) was isolated as the slower moving isomer bypreparative TLC as described in Example 356b.

m.p. 71°-75° C., R_(f) (SiO₂)=0.20 (CH₂ Cl₂ --MeOH--NH₄ OH 8:2:0.2).

Mass Spec. 588 (M+H)⁺.

EXAMPLE 358 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-(2-hydroxy-2-methylpropoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 358b)

(a) Compound 358a ##STR815##

Compound 346a was reacted with CH₃ MgBr by a procedure analogous to thatof Example 158a to give Compound 358a.

(b) Compound 358b ##STR816##

Compounds 358a and 16b were reacted by a procedure analogous to that ofExample 226b to give the title Compound 358b (white solid).

m.p. 85°-88° C.; [α]_(D) =-4.5° (c=0.11, CH₃ OH)

Mass Spec. (FAB): (M+H)=632.

EXAMPLE 359 Preparation of[1R*,2S*(2S*,3R*)]-N-[2-Hydroxy-3-[[2-hydroxy-3-[[(2-hydroxy-1,1-dimethylethoxy)carbonyl]amino]-4-phenylbutyl]amino-1-(phenylmethyl)propyl]-N²-(2-methoxycarbonyl)-3-methyl-L-valinamide (Compound 359b)

(a) Compound 359a ##STR817##

To a 0° C. solution of Compound 246a (0.036 g, 0.191 mmol) in 3 mL ofCH₂ Cl₂ was added HOBT-hydrate (0.035 g, 0.261 mmol) followed by EDCI(0.037 g, 0.191 mmol). The mixture was stirred at 0° C. for 0.5 h andCompound 333b (0.1 g, 0.174 mL) was added followed by N-methylmorpholine(0.058 mL, 0.522 mmol) and 0.5 mL of DMF. The resulting solution wasstirred at RT for 20 h. The mixture was diluted with EtOAc and washedwith sat. NaHCO₃ and brine. The organic phase was dried (MgSO₄) andconcentrated in vacuo. The residue obtained was flash chromatographed onsilica gel eluting with a stepwise gradient of 98.9:1:0.1 to 89:10:1 CH₂Cl₂ --MeOH--NH₄ OH to afford Compound 359a (0.096 g, 74%) as a whitesolid.

Mass Spec (FAB)--(M+H)⁺ =745.

(b) Compound 359b ##STR818##

A solution of Compound 359a (0.095 g, 0.127 mmol) in 3 mL of 3:1:1HOAc-THF-H₂ O was stirred at RT for 16 h. The mixture was concentratedin vacuo and flash chromatographed twice on silica gel eluting with astepwise gradient of 98.9:1:0.1 to 89:10:1 CH₂ Cl₂ --MeOH--NH₄ OH toobtain a solid which was triturated twice with Et₂ O to afford Compound359b (0.07 g, 87%) as a white solid.

m.p. 93°-104° C.; [α]_(D) =-21.2° (c=0.2, CH₃ OH).

Mass Spec. (FAB): (M+H)⁺ =631

Analysis calc. for C₃₃ H₅₀ N₄ O₈ . 3.03 H₂ O: C, 57.83; H, 8.24; N, 8.18Found: C, 57.92; H, 7.66; N, 8.09.

EXAMPLE 360 Preparation of[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]bis[carbamicacid], 1,1-dimethylethyl tetrahydro-1,1-dioxo-3-thienyl ester (Compound360c)

(a) Compound 360a ##STR819##

Compound 360a was prepared from tetrahydrothiophene-3-one in two stepsemploying the procedure described in Dodd et al., J. Heterocyclic.Chem., 27, 1453 (1990).

(b) Compound 360b ##STR820##

Compound 360a was converted to Compound 360b by a procedure analogous tothat of Example 149d.

(c) Compound 360c ##STR821##

Compounds 360b and 54 were converted to the title Compound 360c (whitesolid) in 13% yield by a procedure analogous to that of Example 147d(DMF only used).

m.p. 197°-201° C.

Mass Spec. (FAB): 606 (M+H⁺)

Analysis calc. for C₃₀ H₄₃ N₃ O₈ S: C, 59.49; H, 7.15; N, 6.94; S, 5.29Found: C, 59.44; H, 7.17; N, 7.07; S, 5.23.

EXAMPLE 361 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2,2-Dimethyl-1-hydroxycyclohexyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A (Compound 361b)

(a) Compound 361a ##STR822##

2,2-Dimethylcyclohexanone was converted to Compound 361a by a three-stepprocedure analogous to that used for the preparation of Compound 321c.

(b) Compound 361b ##STR823##

Compounds 361a and 54 were reacted by a procedure analogous to that ofExample 321d. The crude product was chromatographed on a 2.5×25 cmsilica gel column as follows: 1% MeOH/CH₂ Cl₂ ; 2% MeOH/CH₂ Cl₂ ; 2.5%MeOH/CH₂ Cl₂ ; 3-4.75% MeOH/CH₂ Cl₂ +0.3-0.75% NH₄ OH in 0.25% and0.025% increments respectively. The faster moving isomer was furtherpurified by preparative HPLC (UV 220; YMC S-10 ODS (C-18) 30×500 mmcolumn; stepwise gradient from 76-86% MeOH/H₂ O+0.1% TFA) followed bychromatography on a 2.5×5 cm silica gel column using 5% MeOH/CH₂ Cl₂+0.5% NH₄ OH to give 59 mg (17%) of the title Compound 361b as a whitesolid.

m.p 175°-180° C.; R_(f) =0.20, CH₂ Cl₂ :MeOH:NH₄ OH, 90:9:1 (UV and PMAdetection); [α]_(D) =+6.2° (C 0.42, MeOH).

Mass Spec. CI+ions: M+H=598.

Analysis calc. for C₃₄ H₅₁ N₃ O₆ : C, 68.31; H, 8.60; N, 7.03; Found C,68.38; H, 8.80; N, 7.08.

EXAMPLE 362 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2,2-Dimethyl-1-hydroxycyclohexyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer B (Compound 362) ##STR824##

The slower moving isomer of Example 361b was further purified bypreparative HPLC (UV 220; YMC S-10 ODS (C-18) 30×500 mm column; stepwisegradient from 76-86% MeOH/H₂ O+0.1% TFA) followed by chromatography on a2.5×5 cm silica gel column using 5% MeOH/CH₂ Cl₂ +0.5% NH₄ OH to afford50 mg (15%) of Compound 362 as a white solid.

m.p. 101°-105° C.; R_(f) =0.17, CH₂ Cl₂ :MeOH:NH₄ OH, 90:9:1 (UV and PMAdetection); [α]_(D) =-4.1° (C 0.49, MeOH).

Mass Spec. FAB+ions: M+H=598.

Analysis calc. for C₃₄ H₅₁ N₃ O₆.0.28 H₂ O: C, 67.74; H, 8.62; N, 6.97;Found C, 67.70; H, 8.57; N, 7.01.

EXAMPLE 363 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-(3-methyl-2-oxo-1-imidazolidinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 363d)

(a) Compound 363a ##STR825##

To a solution of Compound 343a (750 mg; 5.72 mmol) in 572 μL of drybenzene was added SOCl₂ (417 μL; 5.72 mmol). The solution was heated toreflux for 3 h at which time an additional amount of SOCl₂ (83 μL; 1.14mmol) was added to the reaction. After 30 min, NaHCO₃ (576 mg) was addedand the mixture was filtered. The solid residue was washed with 50 mL ofbenzene. The filtrate was treated with charcoal and filtered. Thefiltrate was concentrated in vacuo to afford Compound 363a as a clearbrown oil (580 mg; 68%).

(b) Compound 363b ##STR826##

Compound 363a (424 mg; 2.83 mmol) and methylamine (1.95 mL; 56.6 mmol;40% weight solution in H₂ O) were stirred at RT for 6 d. The reactionmixture was concentrated in vacuo and purified on silica gel using astepwise gradient of 2% to 8% MeOH:CH₂ Cl₂ to afford Compound 363b (333mg; 82%) as a green oil.

(c) Compound 363c ##STR827##

Compounds 175c and 363b were reacted by a procedure analogous to that ofExample 282a to afford Compound 363c.

(d) Compound 363d ##STR828##

Compounds 363c and 16b were reacted by a procedure analogous to that ofExample 226b to give the title Compound 363d as a white solid.

m.p. 63°-66° C.; [α]_(D) =+2.5° (c 0.12, CH₃ OH)

Mass Spec. (FAB): (M+H)=686

EXAMPLE 364 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[tetrahydro-3-hydroxy-4,4-dimethyl-3-furanyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)-propyl]carbamicacid, 1,1-dimethylethyl ester, Isomer A (Compound 364f)

(a) Compound 364a ##STR829##

(D,L)-Pantolactone was converted to Compound 364a by a procedureanalogous to that of Example 306a.

(b) Compound 364b ##STR830##

To a -78° C. solution of Compound 364a (7.50 g; 34.0 mmol) in anhydroustoluene and CH₂ Cl₂ (75 mL each) was added a solution of DIBAL-H (40.90mL of a 1.0M solution in hexanes; 40.9 mmol) over 1 h. The solution wasstirred at -78° C. for 2 h. MeOH (9.0 mL) was added dropwise. Theresulting suspension was allowed to warm to RT. Brine (31 mL) and Et₂ O(1 L) were added, followed by MgSO₄ (70 g). The suspension was stirredfor 1.5 h, and then filtered. The solids were washed with EtOAc and thecombined filtrates were concentrated in vacuo to give a viscous oil,which solidified on standing to give Compound 364b (7.11 g; 94%; 5.4:1mixture of anomers) as a white solid.

(c) Compound 364c ##STR831##

To a -78° C. solution of Compound 364b (5.97 g; 26.8 mmol) in anhydrousCH₂ Cl₂ were successively added Et₃ SiH (12.84 mL, 80.4 mmol), andBF₃.OEt₂ (3.63 mL; 29.5 mmol) dropwise. The solution was stirred at -78°C. for 2 h, then slowly warmed to 0° C. and stirred for 1 h, then cooledto -78° C. NaHCO₃ (9.0 g) was added and the mixture was stirred at -78°C. for 15 min. Saturated aq. NaHCO₃ was added, and the mixture wasallowed to warm to RT over 1 h. The aqueous layer was extracted withEtOAc and the combined organic extracts were dried (MgSO₄), concentratedin vacuo, and purified by flash chromatography (SiO₂ ; 200 mL) using astepwise gradient from 99:1 to 90:10 hexanes:Et₂ O to give Compound 364c(4.89g; 88%) as a colorless oil.

(d) Compound 364d ##STR832##

Compound 364c was converted to Compound 364d by a procedure analogous tothat described in Example 19.

(e) Compound 364e ##STR833##

Compound 364d was converted to Compound 364e by a procedure analogous tothat of Example 314a.

(f) Compound 364f ##STR834##

Compounds 364e and 54 were converted to the title Compound 364f by afour-step procedure analogous to that described in Example 321. Flashchromatography (100 mL SiO₂ ; stepwise gradient from 99:1:0.1 to 90:10:1CH₂ Cl₂ :MeOH:NH₄ OH) followed by preparative HPLC (Polymer Labs PLRP-Scolumn, 25×300 mm, 10 μm particle size, stepwise gradient from 70:30 to45:55 A:B (where A=90:10:0.2 H₂ O:MeCN:NH₄ OH and B=90:10:0.2 MeCN:H₂O:NH₄ OH)), and lyophilization from dioxane-H₂ O gave 19 mg of Compound364f as a white solid.

m.p.=84°-87° C.; [α]=+6.8° (c=0.20, MeOH); R_(f) (SiO₂)=0.29 (90:10:1CH₂ Cl₂ :MeOH:NH₄ OH).

Mass Spec. (CI): (M+H)⁺ =586

Analysis calc. for C₃₂ H₄₇ N₃ O₇.0.78 H₂ O: C, 64.07; H, 8.16; N, 7.01Found: C, 63.99; H, 7.97; N, 7.09.

EXAMPLE 365 Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[tetrahydro-3-hydroxy-4,4-dimethyl-3-furanyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)-propyl]carbamicacid, 1,1-dimethylethyl ester, Isomer B (Compound 365) ##STR835##

Flash chromatography followed by preparative HPLC as described inExample 364f gave 17 mg of the title Compound 365 (white solid).

m.p.=82°-85° C.; [α]=-13.7° (c=0.16, MeOH); R_(f) (SiO₂)=0.19 (90:10:1CH₂ Cl₂ :MeOH:NH₄ OH).

Mass Spec. (CI): (M+H)⁺ =586

Analysis calc. for C₃₂ H₄₇ N₃ O₇.0.69 H₂ O: C, 64.25; H, 8.15; N, 7.02.Found: C, 64.24; H, 8.02; N, 7.03.

EXAMPLE 366

Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-Hydroxy-2-(hydroxymethyl)-3,3-dimethyl-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A (Compound 366d)

(a) Compound 366a ##STR836##

To a solution of 80% m-CPBA (8.5 g, 39.41 mmol) in 160 mL CH₂ Cl₂ wasadded Compound 262a (3 g, 26.27 mmol) in 30 mL CH₂ Cl₂ (40 mL) and themixture stirred at RT for 20 h. The reaction mixture was cooled to 0° C.and quenched by addition of Me₂ S (6 mL) and washed with 10% aq. Na₂CO₃. The aqueous phase was extracted with CH₂ Cl₂, and the combinedorganic layer dried (Na₂ SO₄), filtered and the solvent removed bydistillation. Fractional distillation (10-23 mm, 70°-90° C.) of theresidue afforded Compound 366a (2.63 g, 77% yield) as a light yellowliquid.

(b) Compound 366b ##STR837##

To Compound 366a (2.47 g, 18.97 mmol) in CH₃ CN (65 mL), was added 0.85mL H₂ O, followed by NaIO₄ (12.17 g, 56.92 mmol) and RuCl₃ (86.5 mg,0.417 mmol) and the slurry stirred at RT for 2-3 min, after whichanother 0.85 mL H₂ O was added and the mixture stirred at RT for 2 h.The reaction mixture was diluted with Et₂ O, filtered through celite andthe filtrate concentrated in vacuo. The resulting residue was dissolvedin 1N NaOH (pH ca. 12), extracted with Et₂ O and the aqueous layerseparated and acidified (pH 3.0) by addition of 3N HCl. Saturation ofthe aqueous phase with Na₂ SO₄, and extraction with EtOAc affordedCompound 366b (1.58 g, 58% yield) as a brown oil.

(c) Compound 366c ##STR838##

To Compound 366b (1.58 g, 10.97 mmol) in H₂ O (55 mL), was added 10% H₂SO₄ (25 mL) and the mixture heated at 100°-105° C. for 8 h. The mixturewas cooled to RT, saturated with Na₂ SO₄ and extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄) and concentrated in vacuo.The residue was purified by silica gel chromatography, eluting with80:20:0.2 to 0:100:1 hexane:EtOAc:HOAc to afford Compound 366c (276 mg,16% yield) as a white solid.

(d) Compound 366d ##STR839##

To a solution of Compound 54 (300 mg, 0.676 mmol) in DMF (1.5 mL) wasadded a solution of Compound 366c (120 mg, 0.743 mmol) in 0.3 mL DMF,followed by BOP reagent (329 mg, 0.743 mmol) and N-methylmorpholine (164μL, 1.48 mmol) at 0° C. The mixture was heated at 50° C. for 24 h, andthen stirred at RT for another 24 h. DMF was removed in vacuo and theresidue dissolved in EtOAc, washed with saturated NaHCO₃ and then withbrine. The organic layer was separated, dried (MgSO₄) and concentratedin vacuo to afford the crude product as a mixture of diastereomers.Combination with material from a prior reaction (0.113 mmol scalereaction) and chromatography on silica gel, eluting with 99:1:01 to92:8:0.8 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH gave Compound 366d as the fastermoving isomer. Further purification by preparative HPLC (Polymer LabsPLRP-S 100 Å, 10μ column, stepwise gradient [65:35 C:D to 55:45 C:D (1h); C=10% CH₃ CN/H₂ O+0.2% aq. NH₄ OH; D=90% CH₃ CN/H₂ O+0.2% aq. NH₄OH]) gave the title Compound 366d (13 mg, 3%) as a white solid.

m.p. 83°-85° C.; R_(f) (SiO₂)=0.4 (90:10:1 CH₂ Cl₂ :MeOH:NH₄ OH).

Mass spectrum (Fab): (M+H)⁺ 588⁺.

EXAMPLE 367

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-Hydroxy-2-(hydroxymethyl)-3,3-dimethyl-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer B (Compound 367) ##STR840##

The slower moving isomer from Example 366d was purified by preparativeHPLC in analogy to Compound 366d to afford Compound 367 as a whitesolid.

m.p. 84°-86° C.; R_(f) (SiO₂)=0.3 (90:10:1 CH₂ Cl₂ :MeOH:NH₄ OH).

Mass spectrum (Fab): (M+H)⁺ 588⁺.

EXAMPLE 368

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,2-Dimethyl-1-hydroxycyclopentyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 2-hydroxy-1,1-dimethylethyl ester, isomer A (Compound 368f)

(a) Compound 368a ##STR841##

To an ice cooled solution of 1.75 g (3 mmol) of Compound 45 and 1.03 ml(6 mmol) of i-Pr₂ NEt in 10 ml of DMF was added dropwise 470 μl (3.3mmoles) of benzyl chloroformate, neat. Stirring was continued withcooling for 0.5 h, then at RT overnight. The solution was evaporated todryness and the residue purified by flash chromatography on a 1250 cccolumn of silica gel. Elution with 40% EtOAc - hexane afforded 2.0 g(94%) of Compound 368a as a white solid.

TLC (SiO₂) R_(f) =0.14 (1:1 EtoAc/Hexane).

(b) Compound 368b ##STR842##

To 1.88 g (2.64 mmol) of Compound 368a at 0° C. was added 10 ml of 4NHCl-dioxane. The reaction was stirred with cooling until solution wasobtained, then at RT for an additional 3 h. The reaction mixture wasevaporated to dryness and the residue evaporated twice from MeOH toafford 1.54 g (90%) of Compound 368b as a white solid.

TLC (SiO₂) R_(f) =0.33 (10% MeOH/CHCl₃).

(c) Compound 368c ##STR843##

A solution of 1.38 g (2.13 mmol) of Compound 368b, 0.86 g (2.34 mmol) ofCompound 161d, and 2.2 ml of i-Pr₂ NEt in 10 ml of DMF was stirred at RTfor 5 d. The solution was evaporated to dryness and the residuedissolved in EtOAc. The solution was washed with 1N HCl, brine, 1N NaOH,and brine and dried (MgSO₄). After removal of solvent, the residue waspurified by flash chromatography on a 500 cc column of silica gel.Elution with 25% EtOAc - hexane, followed by 50% EtOAc - hexane afforded1.36 g (76%) of Compound 368c as a solid white foam.

TLC (SiO₂) R_(f) =0.25 (1:1 EtOAc/hexane).

(d) Compound 368d ##STR844##

A solution of 1.0 g (1.19 mmol) of Compound 368c in 20 ml of EtOH washydrogenated over 100 mg of 20% Pd(OH)₂ /C catalyst for 2 h at RT. Tothe reaction was added 1 ml of NH₄ OH and stirring was continued for 0.5h. The catalyst was removed by filtration through Celite and thefiltrate evaporated to dryness to give 717 mg (100%) of Compound 368d asa solid foam.

TLC (SiO₂) R_(f) =0.21 (CHCl₃ :MeOH:aq. NH₄ OH 90:10:1).

(e) Compound 368e ##STR845##

To a solution of 700 mg (1.22 mol) of368d, 193 mg (1.22 mol) of Compound321c, and 148 μl (1.35 mol) of N-methylmorpholine in 5 ml of DMF, withice cooling, was added 597 mg (1.35 mol) of BOP reagent. Stirring wascontinued with cooling for 2 h, then at RT overnight. After removal ofthe DMF (high vac, 30° C.) the residue, in EtOAc, was washed with brineand dried (MgSO₄). The solvent was removed and the residue purified byflash chromatography on a 125 cc column of silica gel. Elution withCHCl₃ :MeOH:NH₄ OH (95:5:0.5) afforded 737 mg (85%) of Compound 368e asa white foam.

TLC(SiO₂) R_(f) =0.39 and 0.34 (CHCl₃ :MeOH:aq. NH₄ OH 90:10:1).

(f) Compound 368f ##STR846##

A solution of 720 mg (1 mmol) of Compound 368e in 10 ml HOAc:H20:THF(3:1:1) was stirred at RT for 48 h. The reaction was evaporated todryness and the clear colorless oil residue dissolved in EtOAc andwashed with sat. aq. NaHCO₃ and with brine and dried (MgSO₄). Removal ofsolvent gave 654 mg of crude material which was purified by flashchromatography on a 125 cc column of silica gel. Elution with CHCl₃:MeOH:NH₄ OH (95:5:0.5) afforded, as the faster moving isomer, Compound368f, which was triturated with CHCl₃ to afford 161 mg (0.27 mmole) ofthe title Compound 368f as a white powder.

m.p. 178°-179° C.; [α]_(D) =+16.0° (c 0.73, MeOH)

R_(f) (SiO₂)=0.20 (CHCl₃ :MeOH:NH₄ OH, 90:10:1).

Mass Spec.: (M+H)⁺ 600⁺.

Analysis calc. for C₃₃ H₄₉ N₃ O₇.0.85 H₂ O: C, 64.45; H, 8.31; N, 6.83.Found: C, 64.20; H, 8.09; N, 7.08.

EXAMPLE 369

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,2-Dimethyl-1-hydroxycyclopentyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 2-hydroxy-1,1-dimethylethyl ester, isomer B (Compound 369)##STR847##

The slower moving isomer from Example 368f was further purified bypreparative HPLC on a YMC S-10 ODS (30×500 mm) column. Gradient elutionfrom 60-90% MeOH-H₂ O+0.1% TFA afforded a white foam which was passedthrough a short column of silica gel (elution with CHCl₃ :MeOH:NH₄ OH,90:10:1) to give 71 mg of Compound 369 as a solid white foam.

m.p. 90°-100° C. (softening at 80°); [α]_(D) =-12.9° (c 0.79, MeOH).

R_(f) (SiO₂)=0.17 (CHCl₃ :MeOH:NH₄ OH, 90:10:1).

Mass Spec.: (M+H)⁺ 600⁺.

Analysis calc. for C₃₃ H₄₉ N₃ O₇.0.40 H₂ O: C, 65.30; H, 8.27; N, 6.92.Found: C, 65.39; H, 8.32; N, 6.83.

EXAMPLE 370

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(2-ethenylphenyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 370c)

(a) Compound 370a ##STR848##

A solution of Compound 349a (1.9 g, 6.8 mmol) in 100 ml of CH₂ Cl₂ wascooled at 0° C. and N-phenyltriflimide (2.67 g, 7.47 mmol) was addedfollwed by Et₃ N (1.15 ml, 8.25 mmol). The reaction was stirred at 0° C.for 2.5 h and then allowed to warm to RT and stir overnight. Additionalquantities of N-phenyltriflimide (800 mg, 2.24 mmol) and Et₃ N (345 ml,2.48 mmol) were added. Stirring was continued for an additional 6 h atRT. The reaction was diluted with Et₂ O and washed with H₂ O, 1N NaOH,H₂ O, and brine. After drying (Na₂ SO₄), the solvents were removed andthe crude material was purified on a 250 ml silica column eluting withEtOAc/hexanes (1:4) to afford 1.6 g (68%) of Compound 370a as acolorless solid.

(b) Compound 370b ##STR849##

To a solution of the Compound 370a (610 mg, 1.5 mmol) in 10 ml of1-methyl-2-pyrrolidinone was added LiCl (190 mg, 4.5 mmol) andtriphenylarsine (90 mg, 0.3 mmol) and the reaction mixture was degassedwith argon. Tris(dibenzylideneacetone)dipalladium (0) (138 mg, 0.15mmol) was added and the mixture stirred for 5 min. Vinyltributyltin(0.520 ml, 560 mg, 1.8 mmol) was added and the reaction mixture was thenstirred for 2.5 h at RT and heated at 55° C. overnight. An additional20% of triphenylarsine (18mg), Pd° (28 mg) and vinyltributyltin (104 ml)were added and heating was continued for an additional 6 h. The mixturewas poured into 1:1 sat. NaHCO₃ /H₂ O and extracted with EtOAc. Thecombined EtOAc extract was washed with H₂ O and brine and dried (Na₂SO₄). The solvent was removed and the crude material was purified on a100 ml silica column eluting with 10 to 20% EtOAc/hexane gradient toafford 190 mg (44%) of Compound 370b as a colorless solid.

(c) Compound 370c ##STR850##

Compounds 370b and 16b were reacted by a procedure analogous to that ofExample 304c to afford the title Compound 370c (colorless solid).

m.p. 173°-176° C. (dec); [α]_(D) =-6.0° (c 0.5, MeOH)

Mass Spec.: (M+H)⁺ 570⁺.

Analysis calc. for C₃₂ H₄₇ N₃ O₆.1.5 H₂ O: C, 64.40; H, 8.40; N, 7.05.Found: C, 64.21; H, 8.03; N, 7.00.

EXAMPLE 371

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(2-ethylphenyl)butyl]amido]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 371) ##STR851##

A solution of Compound 370c (68 mg, 0.12 mmol) in 3 ml of MeOHcontaining 7 mg of 10% Pd/C catalyst was stirred under a hydrogenatmosphere (balloon) for 12 h. The reaction was filtered and the MeOHevaporated to afford 66 mg (98%) of Compound 371 as a colorless solid.

m.p. 178°-181° C. (dec); [α]_(D) =-5.6° (c 0.5, MeOH)

Mass Spec.: (M+H)⁺ 572⁺.

Analysis calc. for C₃₂ H₄₉ N₃ O₆.1.75 H₂ O: C, 63.61; H, 8.91; N, 7.08.Found: C, 63.71; H, 8.77; N, 6.97.

EXAMPLE 372

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[4-[4-[2-[[(Dimethylamino)carbonyl]oxy]ethoxy]phenyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxybutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid (Compound 372d)

(a) Compound 372a ##STR852##

To a stirred solution of phosgene in toluene (8.5 mL of a 1.93Msolution; 16.4 mmol) at -60° C. was added a solution of2-benzyloxyethanol (467 μL, 3.28 mmol) and pyridine (583 μL, 7.22 mmol)in 3 mL CH₂ Cl₂. After adding 20 mL more CH₂ Cl₂, the temperature of thereaction mixture was allowed to rise to 15° C. and was then cooled to-20° C. Excess N,N-dimethylamine was bubbled through the turbid mixturewhich was stirred at RT overnight. The solution was washed with H₂ O,dried (Na₂ SO₄), and concentrated to afford the crude product which waspurified by chromatography on a column (5 cm×15 cm) of silica geleluting with EtOAc-hexane (20-80 to 25-75) to afford 490 mg (67%) ofCompound 372a.

(b) Compound 372b ##STR853##

Compound 372a was converted to Compound 372b by a procedure analogous tothat of Example 208 (EtOH was used instead of MeOH).

(c) Compound 372 c ##STR854##

Compounds 372b and 175c were converted to Compound 372c by a procedureanalogous to that of Example 282a.

(d) Compound 372d ##STR855##

Compounds 372c and 16b were reacted by a procedure analogous to that ofExample 304c to give the title Compound 372d (white solid).

m.p. 128°-132° C.; [α]_(D) =-3.1° (c 0.52, MeOH)

Mass Spec. (FAB), 675 (M+H)⁺.

Analysis calc. for C₃₅ H₅₄ N₄ O₉.0.54 H₂ O: C, 61.41; H, 8.11; N, 8.18.Found: C, 61.40; H, 7.95; N, 8.19.

EXAMPLE 373

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-1,2-dimethylpropyl]carbamicacid, methyl ester, isomer A (Compound 373d)

(a) Compound 373a ##STR856##

Compound 373a was prepared as described in Obrecht et al., Helv. Chim.Acta, 75, 1666 (1992).

(b) Compound 373b ##STR857##

A solution of 1.2 g (7.1 mmol) of 373a in 25 ml of concentrated HCl washeated at 130° C., in a pressure vessel, for 7 d. After cooling to RT,the solution was evaporated to dryness to yield a solid residue whichwas taken into H₂ O, washed with CH₂ Cl₂, and again evaporated todryness to yield 1.6 g of Compound 373b as a tan solid.

(c) Compound 373c ##STR858##

Compound 373b was converted to Compound 373c by a procedure analogous tothat of Example 246a.

(d) Compound 373d ##STR859##

Compounds 373c and 54 were converted to the title Compound 373d by atwo-step procedure analogous to that employed for the synthesis ofCompound 312d (CH₂ Cl₂ only used for reaction of HOBT with Compound373c). The crude product was purified by flash chromatography on a 45 cccolumn of silica gel. Elution with CHCl₃ :MeOH:NH₄ OH (95:5:0.5)afforded 140 mg of a mixture of isomers which were separated bypreparative HPLC on a YMC S-10 ODS (30×500 mm) column. Isocratic elutionwith 70% MeOH-H₂ O+0.1% TFA, gave as the faster moving isomer on C-18,Compound 373d, which was passed through a short column of silica gel(elution with CHCl₃ :MeOH:NH₄ OH (90:10:1)) and triturated with Et₂ O toafford 42 mg (16%) of the title Compound 373d as a white solid.

m.p. 120°-122° C.; [α]_(D) =-0.9° (c 0.66, MeOH)

Mass Spec.: (M+H)⁺ 629⁺.

Analysis calc. for C₃₄ H₅₂ N₄ O₇ : C, 64.94; H, 8.33; N, 8.91. Found: C,64.54; H, 8.13; N, 8.57.

EXAMPLE 374

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-1,2-dimethylpropyl]carbamicacid, methyl ester, isomer B (Compound 374) ##STR860##

The slower moving isomer on C-18 was isolated by preparative HPLC asdescribed in Example 373d followed by passage through a short column ofsilica gel (elution with CHCl₃ :MeOH:NH₄ OH (90:10:1)) and triturationwith Et₂ O to afford 54 mg (20%) of Compound 374 as a white solid.

m.p. 168°-170° C.; [α]_(D) =-21.5° (c 0.75, MeOH)

Mass Spec.: (M+H)⁺ 629⁺.

Analysis calc. for C₃₄ H₅₂ N₄ O₇ : C, 64.94; H, 8.33; N, 8.91. Found: C,64.75; H, 8.33; N, 8.68.

EXAMPLE 375

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,3-Dihydro-1-hydroxy-1H-inden-1-yl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A (Compound 375) ##STR861##

1-Indanone was converted to a 1:1 mixture of Compounds 375 and 376 by afour-step procedure analogous to that used for the synthesis ofCompounds 321 and 322. Compound 375 (while solid) was isolated as thefaster moving isomer by silica gel chromatography, eluding with 99:1:0.1to 94:6:0.6 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH.

m.p. 189°-192° C.; [α]_(D) =-15.7° (c 0.2, CH₃ OH) R_(f) (SiO₂)=0.32(99:1:0.1 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH)

Mass Spec. (Fab): (M+H)⁺ 604.

Analysis calc. for C₃₅ H₄₅ N₃ O₆ : C, 69.63; H, 7.51; N, 6.96. Found: C,69.28; H, 7.5; N, 6.97.

EXAMPLE 376

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,3-Dihydro-1-hydroxy-1H-inden-1-yl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer B (Compound 376) ##STR862##

Compound 376 (white solid) was isolated as the slower moving isomer asdescribed in Example 375.

m.p. 100°-102° C.; [α]_(D) =+15.0° (c 0.22, CH₃ OH)

R_(f) (SiO₂)=0.25 (99:1:0.1 CH₂ Cl₂ :CH₃ OH:aq. N₄ OH)

Mass Spec. (Fab): (M+H)⁺ 604.

EXAMPLE 377

Preparation of[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[2-Hydroxy-1-oxo-2-phenylethyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 377) ##STR863##

To a solution of (R)-mandelic acid (100 mg, 0,225 mmol) in DMF (0.5 mL)was added Compound 54 (37.6 mg, 0.247 mmol), followed by BOP reagent(241 mg, 0.545 mmol) and N-methylmorpholine (132 μL, 1.20 mmol) at 0° C.The mixture was stirred at RT for 16 h. DMF was removed in vacuo and theresidue dissolved in EtOAC, washed with saturated aq. NaHCO₃ and thenwith brine. The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo and the residue purified by silica gelchromatography, eluting with 99:1:0.1 to 91.5:8.5:0.85 CH₂ Cl₂ :CH₃OH:aq. NH₄ OH to afford Compound 377 (94 mg, 72%) as a white solid.

m.p. 125°-127° C.; [α]_(D) =-13.0° (c 0.2, CH₃ OH)

Mass Spec. (Fab): (M+H)⁺ 578⁺.

Analysis calc. for: C₃₃ H₄₃ N₃ O₆.0.80 H₂ O C, 66.93; H, 7.59;N, 7.10.Found: C, 66.76; H, 7.55; N, 7.27.

EXAMPLE 378

Preparation of[1S-[1R*,2S*[2S*,3R*(R*)]]]-[3-[[3-2-Hydroxy-1-oxo-2-phenylethyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 378) ##STR864##

(S)-Mandelic acid and Compound 54 were reacted by a procedure analogousto that of Example 377 to afford the title Compound 378 (white solid).

m.p. 135°-138° C.; [([α]_(D) =+9.1° (c 0.22, CH₃ OH)

Mass Spec. (Fab): (M+H)⁺ 578⁺.

Analysis calc. for: C₃₃ H₄₃ N₃ O₆.0.63 H₂ O C, 67.28; H, 7.57; N, 7.13.Found: C, 67.12; H, 7.54; N, 7.29.

EXAMPLE 379

Preparation of [1S-(1R*,2S*)(trans)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[carbamicacid], 1,1-dimethylethyl 2-hydroxy-1-methylcyclopentyl ester (Compound379e)

(a) Compound 379a ##STR865##

A solution of NaOH (600 mg; 15 mmol) and KMnO₄ (2.81 g; 17.8 mmol) in 95ml of H₂ O precooled to 0° C. was added to a slurry of1-methylcyclopentene (1 g; 12 mmol), t-BuOH (120 ml), H₂ O (25 ml) andice (60 g) at -10° C. The resulting mixture was stirred 10 min at -10°C. Sodium sulfite (2.3 g) was added and the mixture was filtered throughcelite. The filtrate was concentrated to ˜30 ml by distillation of thesolvents at atmospheric pressure. Solid NaCl was added to saturation andthe mixture was extracted with EtOAc. After drying (MgSO₄), the organiclayer was concentrated to afford 1.03 g (74%) of racemic Compound 379a.

(b) Compound 379b ##STR866##

Compound 379a was converted into racemic Compound 379b by a procedureanalogous to that of Example 264b.

(c) Compound 379c ##STR867##

Compound 379b was converted into racemic Compound 379c by a procedureanalogous to that of Example 161d.

(d) Compound 379d ##STR868##

Compounds 379c and 298a were reacted by a two-step procedure analogousthat that used for the conversion of Compound 282c to Compound 282e toafford Compound 379d.

(e) Compound 379e ##STR869##

Compounds 379d and 1b(i) were reacted by a two-step procedure analogousto that used for the conversion of Compound 282e to Compound 282g toafford the title Compound 379e (white solid).

m.p. 102°-113° C. ("shrinkage at 68°-87° C.);

Mass Spec. (FAB) (M+H)⁺ =586.

Analysis calc. for C₃₂ H₄₆ N₃ O₇.0.98H₂ O: C, 63.81; H, 8.02; N, 6.98Found: C, 63.81; H, 8.17; N, 6.98.

EXAMPLE 380

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[2-(3-oxo-4-morpholinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester (Compound 380d)

(a) Compound 380a ##STR870##

To a 0° C. solution of diethanolamine (2.10 g; 20.0 mmol) in 40 mL ofdry CH₂ Cl₂ was added dry Et₃ N (4.2 mL; 30.0 mmol) and bromoacetylbromide (2.1 mL; 24.0 mmol). The reaction mixture was stirred at 5° C.for 3 h, then at RT overnight. Volatiles were removed in vacuo and theresidue was purified on silica using 100% EtOAc to afford 1.5 g of pureCompound 380a (33%).

(b) Compound 380b ##STR871##

To a suspension of Nail (260 mg; 6.63 mmol; 60% in mineral oil) in 1.0mL of dry DMF at 0° C. was added a solution of Compound 380a (1.5 g;6.63 mmol) in 5.5 mL of dry DMF. The solution was allowed to warm to RT.After 6 h another 260 mg (6.63 mmol) of Nail was added and the mixturewas stirred overnight. The reaction was quenched with H₂ O andconcentrated in vacuo to give crude material which was purified onsilica gel using a stepwise gradient from 2% to 8% MeOH:CH₂ Cl₂ :0.1%NH₄ OH to afford Compound 380b (600 mg; 62%).

(c) Compound 380c ##STR872##

Compounds 175c and 380b were reacted by a procedure analogous to that ofExample 282a to give Compound 380c.

(d) Compound 380d ##STR873##

Compounds 16b and 380c were reacted by a procedure analogous to that of304c to give the title Compound 380d (white solid).

m.p. 108°-111° C.; [α]_(D) =-3.3° (c 0.03, CH₃ OH)

Mass Spec. (FAB): (M+H)=687.

EXAMPLE 381

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-hydroxy-1-oxo-2-(2-pyridinyl)propyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A (Compound 381b)

(a) Compound 381a ##STR874##

ZnI₂ (96 mg; 0.3 mmol) was added to a solution of 2-acetylpyridine (1.10ml; 9.8 mmol) and trimethylsilylcyanide (1.70 ml; 12.7 mmol) in 20 ml ofCH₂ Cl₂ at 20° C. After stirring at RT for 3 h, the solvent was removedin vacuo and the residue was stirred in ˜4 ml of concentrated HCl at RTfor 40 h. After cooling to 0° C., the pH of the reaction mixture wasadjusted to 9 with 6N NaOH. The basic mixture was washed with EtOAc,concentrated to ˜15 ml and loaded onto an HP-20 column, eluting withwater, to afford 940 mg (50%) of Compound 381a as a white solid.

(b) Compound 381b ##STR875##

Compounds 54 and 381a were reacted by a procedure analogous to thatdescribed in Example 321d to afford a 1:1 mixture of Compounds 381b and382. The diastereomers were separated by preparative HPLC [YMC S-10 ODS(C-18) 30×500 mm column; stepwise gradient from 56-74% MeOH/H₂ O+0.1%TFA]. Final isolation of the faster moving isomer by chromatography on a2.5×10 cm silica gel column using 5% MeOH/CH₂ Cl₂ +0.5% NH₄ OH as themobile phase gave 88 mg (33%) of the title Compound 381b as a whitesolid.

m.p. 114°-117° C. (softens at 92° C.); R_(f) (SiO₂)=0.25, CH₂ Cl₂:MeOH:NH₄ OH, 90:9:1 (UV and PMA detection); [α]_(D) =-7.8 (c 0.32,MeOH).

Mass Spec. FAB: M+H=593.

Analysis calc. for C₃₃ H₄₄ N₄ O₆.0.49 H₂ O: C, 65.90; H, 7.54; N, 9.31;Found C, 66.10; H, 7.45; N, 9.11.

EXAMPLE 382

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-hydroxy-1-oxo-2-(2-pyridinyl)propyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester isomer B (Compound 382) ##STR876##

Compound 382 (white solid) was isolated as the slower moving isomer bypreparative HPLC followed by silica gel chromatography as described inExample 381b.

m.p. 92°-96° C.; R_(f) (SiO₂)=0.06, CH₂ Cl₂ :MeOH:NH₄ OH, 90:9:1 (UV andPMA detection); [α]_(D) =-5.7° (c 0.30, MeOH).

Mass Spec. FAB: M+H=593.

Analysis calc. for C₃₃ H₄₄ N₄ O₆.0.26 H₂ O: C, 66.34; H, 7.51; N, 9.38;Found C, 66.46; H, 7.65; N, 9.26.

EXAMPLE 383

Preparation of[1R*,2S*[2S*,3R*(S*)]]-N-[2-Hydroxy-3-[[2-hydroxy-3-[(2-hydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]-N.sup.2-(2-methoxycarbonyl)-3-methyl-L-valinamide (Compound 383e)

(a) Compound 383a ##STR877##

To a solution of Compound 298a (500 mg, 2.42 mmol) in 0.5 mL DMF wasadded Compound 246a (505 mg, 2.66 mmol), followed by HOBT hydrate (360mg, 2.66 mmol), N-methylmorpholine (318 mg, 3.15 mmol) and EDCIhydrochloride (510 mg, 2.66 mmol) an 0° C., and the mixture stirred atRT for 21 h. DMF was removed in vacuo and the residue dissolved inEtOAc, washed with sat. NaHCO₃ and then brine. The organic layer wasseparated, dried (MgSO₄) and concentrated to yield a residue which waspurified by silica gel chromatography, eluting from 99.5:0.5:0.05 to96.5:3.5:0.35 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH to afford Compound 383a (604mg, 66%) as a white solid.

TLC (SiO₂), R_(f) =0.41 (9:1:0.1 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH - Rydon).

(b) Compound 383b ##STR878##

To Compound 383a (604 mg, 1.60 mmol) in THF (7 mL) and H₂ O (43 μL) wasadded Ph₃ P (462 mg, 1.76 mmol) and the solution stirred at RT for 18 h.The solvent was removed in vacuo and the resulting residue purified byflash chromatography on silica gel, eluting with a step wise gradientfrom 99:1:0.1 to 87:13:1 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH to afford Compound383b (478 mg, 85%) as a white solid.

TLC (SiO₂) R_(f) =0.15 (9:1:0.1 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH - Rydon).

(c) Compound 383c ##STR879##

To a solution of Compound 383b (468 mg, 1.33 mmol) in DMF (0.6 mL) wasadded Compound 44a (396 mg, 1.33 mmol) and the mixture heated at 100° C.for 7 h. DMF was removed in vacuo and the residue purified by flashchromatography on silica gel, eluting with a step wise gradient from99:1:0.1 to 82:12:1 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH to afford Compound 383c(377 mg, 43%) as a white solid.

TLC (SiO₂) R_(f) =0.28 (9:1:0.1 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH/Rydon).

(d) Compound 383d ##STR880##

To a solution of Compound 383c (366 mg, 0.564 mmol) in EtOH (12 mL) andEtOAc (4 mL) was added 20% Pd(OH)₂ /C (108 mg) and the slurry stirredunder a H₂ (g) atmosphere for 18 h. The reaction mixture was filteredand the filtrate concentrated in vacuo. The residue was purified byflash chromatography on silica gel, eluting with a step wise gradientfrom 97.5:2.5:0.25 to 87:13:1 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH to affordCompound 383d (209 mg, 7 6% ) as a white solid.

TLC (SiO₂) R_(f) =0.14 (9:1:0.1 CH₂ Cl₂ :CH₃ OH:aq. NH₄ OH/Rydon).

(e) Compound 383e ##STR881##

To a solution of Compound 383d (105 mg, 0.204 mmol) in DMF (0.5 mL ) wasadded Compound 262e (34.5 mg, 0.236 mmol), followed by BOP reagent (104mg, 0.236 mmol) and N-methylmorpholine (52 μL, 0.473 mmol) and themixture stirred at RT for 18 h. DMF was removed in vacuo, the residuedissolved in EtOAc and washed with sat. NaHCO₃ and then brine. Theorganic layer was separated, dried (MgSO₄) and concentrated in vacuo.Purification was achieved by flash chromatography on silica gel, elutingwith a step wise gradient from 97.5:2.5:0.25 to 87:13:1 CH₂ Cl₂ : CH₃OH:aq. NH₄ OH to afford the title Compound 383e (70 mg, 54% yield) as awhite solid.

m.p. 94°-96° C.; [α]_(D) =+4.54° (c 0.22, CH₃ OH)

Mass Spec. (Fab): (M+H)⁺ 643⁺.

Analysis calcd. for C₃₅ H₅₄ N₄ O₇.1.00 H₂ O C, 63.62; H, 8.54; N, 8.72.Found: C, 63.70; H, 8.43; N, 8.40.

EXAMPLE 384

Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-Hydroxy-3,3-dimethyl-2-[(methylamino)carbonyl]-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A (Compound 384d)

(a) Compound 384a ##STR882##

Diazomethane in Et₂ O (prepared from 5.45 g of1-methyl-3-nitro-1-nitrosoguanidine as described in Example 1a(i)) wasadded to a suspension of Compound 366c (3.0 g, 18.5 mmol) in 50 mL ofEt₂ O at 0° C. The resulting mixture was quenched with few drops of HOAcand concentrated in vacuo to afford Compound 384a (oil; 3.26 g, 100%crude yield).

(b) Compound 384b ##STR883##

Compound 384a was converted to Compound 384b by a two-step procedureanalogous to that used for the synthesis of Compound 262e.

(c) Compound 384c ##STR884##

A mixture of methylamine (ca. 5 g) and Compound 384b (0.9 g, 4.74 mmol)in 10 mL of MeOH was heated in a sealed tube at 150° C. for 3 h andconcentrated in vacuo. The residue was dissolved in CH₂ Cl₂, washed with20% aq. sulfuric acid, the combined aqueous phase was extracted with CH₂Cl₂, and the combined organic phase was dried (MgSO₄) and concentratedto afford the Compound 384c (0.55 g, 61%) as a colorless oil.

(d) Compound 384d ##STR885##

Compounds 384c and 54 were converted to the title Compound 384d and itsdiastereomer Compound 385 by a two-step procedure analogous to thatemployed for the synthesis of Compound 312d (CH₂ Cl₂ only was used forthe reaction of HOBT with Compound 384c). The mixture was purified byflash chromatography (silica gel/CH₂ Cl₂ --MeOH--NH₄ OH 99:1:0.1 to95:5:0.5) to afford 115 mg of a 1:1 mixture of diastereomers which wereseparated by preparative HPLC (column: Polymer Labs. PLRP-S 100 A 10 μm25×300 mm; eluent: 30:70 step wise to 1:1 A:B, eluent A=H₂ O--CH₃CN--NH₄ OH 90:10:0.2, eluent B=H₂ O--CH₃ CN--NH₄ OH 10:90:0.2) to affordthe title Compound 384d (faster moving isomer on polymer column) as awhite solid (25 mg, 9% yield).

R_(f) =0.37 (silica gel/CH₂ Cl₂ --MeOH--NH₄ OH 9:1:0.1),

m.p. 77°-78° C., [α]_(D) =-7.5° (c 0.6 MeOH).

Mass Spec.: 615 (M+H)⁺.

Analysis calcd for C₃₃ H₅₀ N₄ O₇.0.77 H₂ O: C, 63.05; H, 8.26; N, 8.91.Found: C, 63.24; H, 8.17; N, 8.91.

EXAMPLE 385

Preparation of[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-Hydroxy-3,3-dimethyl-2-[(methylamino)carbonyl]-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer B (Compound 385) ##STR886##

Compound 385 (white solid) was isolated (slower moving isomer on polymercolumn) by preparative HPLC as described in Example 384d.

R_(f) =0.37 (silica gel/CH₂ Cl₂ --MeOH--NH₄ OH 9:1:0.1),

m.p. 76°-77° C.; [α]_(D) =-15.1° (c 0.55 MeOH).

Mass Spec.: 615 (M+H)⁺.

Other compounds contemplated by the present invention include thefollowing compounds:

1.[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl 3,3,3-trifluoro-2-hydroxy-1,1-dimethylpropylester.

2.[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl (R,R:S, S)-2-hydroxy-1-methylcyclopentyl ester.

3.[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl (R,S:S,R)-tetrahydro-4-hydroxy-3-furanyl ester.

4.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(1-hydroxy-2,2-dimethylcyclobutyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

5.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(4-hydroxyspiro[2.4]hept-4-yl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

6.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(5-hydroxyspiro[3.4]oct-5-yl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

7.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(6-hydroxyspiro[4.4]non-6-yl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

8.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(octahydro-1-hydroxy-1-pentalenyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

9.[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamicacid, 1,1-dimethylethyl tetrahydro-4,4-dimethyl-3-furanyl ester.

10.[1S-[1R*,2S*(2S*,3R-*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(1,5-dihydroxy-2,2-dimethylcyclopentyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

11.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(1,4-dihydroxy-2,2-dimethylcyclopentyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

12.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-hydroxy-1-oxo-2-(3-pyridinyl)propyl]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

13.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2,3,3-trimethyl-2-[(methylamino)carbonyl]-1-oxobutyl]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

14.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-cyano-2,3,3-trimethyl-1-oxobutyl]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

15.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-cyano-3,3-dimethyl-1-oxobutyl]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

16.[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[4-hydroxy-2-[(methoxycarbonyl)amino]-3,3-dimethyl-1-oxobutyl]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

17.[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[2-(hydroxymethyl)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester.

18.[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[2-(2-hydroxyethyl)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid,1,1-dimethylethyl ester.

19.[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[2-(3-hydroxypropyl)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid,1,1-dimethylethyl ester.

20.[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[[(4-morpholinylcarbonyl)oxy]methyl]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]carbamicacid, 1,1-dimethylethyl ester.

21.[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-[3-(4-morpholinyl)-3-oxopropyl]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamicacid, 1,1-dimethylethyl ester.

The above compounds correspond (by number) to the following structures:##STR887##

HIV Protease Assay

An HIV protease standard assay was performed in a 60 μl reaction mediumcontaining 50 mM sodium acetate, pH 5.5, 100 μg/ml bovine serum albumen,450 μM substrate (H₂N-Val-Ser-Gln-Asn-(β-naphthylalanine)-Pro-Val-Ile-OH), and purifiedprotease. The reaction medium was incubated for 30 minutes at 37° C.,quenched by the addition of 140 μl 5% H₃ PO₄, then analyzed by reversephase HPLC using UV₂₂₀ detection. In a typical control assay, 7% of thesubstrate was hydrolyzed. Aminediol inhibitors of the present invention,listed in the following Table 1, were then employed in the assay, forwhich purpose they were prepared as a 0.5 mM solution in DMSO, thendiluted to 30 μM with 50 mM sodium acetate/bovine serum albumen. Thisworking stock was then diluted three-fold into the protease reactionmedium, for a final concentration of 10 μM inhibitor and 4% DMSO. Theresults obtained from the assay are shown in the following Table 1.

Cell Culture Anti-HIV Activity

The antiviral activity of aminediol inhibitors of the present inventionwas evaluated by a microculture method which determines the increase incell viability of an infected culture when a drug is added. The assaydepends on the metabolic reduction of tetrazolium reagent by viablecells to yield a soluble colored formazan product.

The assay was performed as follows: suspensions of CEM-SS cells(5000/well) were infected with the RF strain of HIV at a multiplicity ofinfection at 0.04 in a 96-well plate. The compounds of the presentinvention listed in the following Table 1, serially diluted in half-logfashion, were added to the infected and uninfected control cells.Untreated (infected and uninfected) cells were included as controls.Following incubation for 6 days at 37° C., viable cells in each wellwere quantitated by the visible light absorbance at 450 nm.

The IC₅₀ was calculated as the concentration of drug that increased theformazan production in virally infected cells to 50% of that produced byuninfected cells in the absence of drug. The results obtained in theassay are shown in the following Table 1.

                  TABLE 1                                                         ______________________________________                                                  HIV Protease    HIV (CEM Cells)                                     Compound  % Inhibition at 10 μM                                                                      IC.sub.50 (μM)                                   ______________________________________                                        2         100             0.09                                                3         0               >3.2                                                5         41              2.8                                                 7         8               ND                                                  8         2               ND                                                  10        1               ND                                                  11        0               >6                                                  12        1               ND                                                  13        45              5.3                                                 14        100             1.1                                                 15        98              0.38                                                16        83              ≧2.3                                         17        84              >1.5                                                21        99              0.09                                                22        90              >1.8                                                23        98              0.45                                                24        78              4.5                                                 25        98              0.53                                                26i       57              ND                                                  26ii      41              ND                                                  27        19              ND                                                  28        100             0.09                                                29        100             0.1                                                 30        97              0.5                                                 31        100             0.03                                                34        20              >9                                                  36        36              >8                                                  38        3               >4                                                  42        100             0.6                                                 43        21              ND                                                  44        58              >5                                                  45        87              0.5                                                 47        81              1.1                                                 50        97              0.22                                                52        100             0.2                                                 53        99              0.54                                                55        91              0.7                                                 56        47              ND                                                  57        46              ND                                                  58        57              1.0                                                 59        45              ND                                                  60        78              1.2                                                 62        98              0.05                                                63        53              ND                                                  64        72              >5                                                  65        11              ND                                                  66        99              0.27                                                67        100             0.04                                                68        99              0.11                                                69        11              ND                                                  70        100             0.5                                                 71        58              1.2                                                 72        51>             3.2                                                 73        99              0.6                                                 75        100             5.0                                                 76        100             0.6                                                 77        99              0.2                                                 78        99              0.16                                                79        99              0.4                                                 80        98              0.3                                                 82        94              >3                                                  83        19              ND                                                  84        99              1.2                                                 86        78              1.8                                                 87        92              >0.88                                               88        100             0.03                                                89        23              ND                                                  92        100             39                                                  93        100             0.18                                                94        80-99           ND                                                  96        100             >7.6                                                98        100             1.3                                                 99        99              >100                                                100       99              0.23                                                101       99              0.14                                                102       47              ND                                                  103       98              1.7                                                 104       99              0.03                                                105       99              1.6                                                 106       71              ND                                                  112       100             >8.6                                                115       58              ND                                                  117       14              ND                                                  119       10              ND                                                  121       73              >0.3                                                123       65              1.0                                                 125       71              >1.5                                                127       15              ND                                                  132       65              >3                                                  134       87              >5                                                  136       73              ND                                                  137       92              >2.6                                                138       98              >0.8                                                139       73              ND                                                  140       61              ND                                                  141       77              >2.3                                                142       30              ND                                                  144       88              1.0                                                 145       95              >2.2                                                146       98              ≧3.0                                         148       88              2.0                                                 150       93              >4.0                                                153       65              >0.55                                               154       96              >1.2                                                155       95              >0.2                                                156       85              >6.0                                                157       90              ND                                                  158       97              >1.8                                                159       100             1.3                                                 160       99              0.08                                                164       99              0.04                                                165       100             0.62                                                166       89              1.7                                                 167       97              >1.8                                                168       61              1.4                                                 169       97              0.2                                                 170       100             0.1                                                 171       99              0.05                                                175       99              0.03                                                178       99              0.03                                                179       99              0.17                                                180       73              ND                                                  181       46              ND                                                  182       41              ND                                                  183       35              ND                                                  184       99              1.3                                                 185       5               ND                                                  186       0               ND                                                  187       28              ND                                                  188       21              ND                                                  189       23              ND                                                  190       <16             ND                                                  191       13              ND                                                  192       85              ND                                                  193       66              ND                                                  194       0               >5.0                                                195       0               ND                                                  196       6               ND                                                  197       10              >10                                                 198       10              >14                                                 199       3               >17                                                 200       5               >15                                                 201       99              0.04                                                202       95              16                                                  203       98              0.2                                                 204       99              0.17                                                205       98              0.07                                                209       99              0.03                                                210       81              >5                                                  211       99              0.9                                                 212       99              3.8                                                 213       98              0.17                                                214       97              0.05                                                215       66              ND                                                  216       49              ND                                                  217       100             0.48                                                218       96              1.6                                                 219       86              3 5                                                 220       100             0.77                                                221       96              1.1                                                 222       98              0.38                                                223       89              1.4                                                 224       98              0.04                                                225       99              0.5                                                 226       98              0.05                                                227       99              0.9                                                 228       98              0.7                                                 229       82              0.6                                                 230       92              4.9                                                 231       83              ND                                                  232       99              0.05                                                233       100             1.0                                                 234       100             0.08                                                235       97              0.35                                                236       89              0.7                                                 237       54              ND                                                  238       64              2.3                                                 239       37              ND                                                  240       99              2.0                                                 241       95              0.28                                                242       99              0.11                                                243       99              0.08                                                244       100             1.5                                                 245       100             1.8                                                 246       100             0.04                                                247       99              0.1                                                 248       99              0.23                                                249       100             0.84                                                250       100             1.5                                                 251       98              ND                                                  252       99              0.06                                                253       85              ND                                                  254       98              17                                                  255       86              ND                                                  256       88              1.5                                                 257       99              0.03                                                258       91              1.5                                                 259       99              5.0                                                 260       100             0.29                                                261       94              1.1                                                 262       100             0.03                                                263       98              0.34                                                264       99              0.16                                                265       100             2.6                                                 266       69              ND                                                  267       97              0.18                                                268       94              ND                                                  269       61              ND                                                  270       27              ND                                                  271       99              0.06                                                272       87              ND                                                  273       100             1.7                                                 274       99              ND                                                  275       95              0.45                                                276       97              0.13                                                277       67              ND                                                  278       94              0.84                                                279       54              ND                                                  280       100             0.05                                                281       100             0.29                                                282       100             0.06                                                283       100             0.11                                                284       100             4.4                                                 285       100             0.65                                                286       99              5.0                                                 287       89              ND                                                  288       100             0.47                                                289       53              ND                                                  290       99              0.06                                                291       73              ND                                                  292       99              0.17                                                293       99              0.03                                                294       89              ND                                                  295       82              ND                                                  296       37              ND                                                  297       100             0.05                                                298       100             0.06                                                299       99              0.24                                                300       99              0.03                                                301       95              2.4                                                 302       99              0.25                                                303       98              0.07                                                304       99              0.03                                                305       100             0.2                                                 306       100             0.06                                                308       100             0.02                                                309       100             1.8                                                 310       100             0.18                                                311       100             0.05                                                312       95              3.5                                                 313       65              ND                                                  314       100             0.12                                                315       100             1.6                                                 316       97              0.62                                                317       85              ND                                                  318       100             0.1                                                 319       93              1.37                                                320       100             0.22                                                321       100             0.2                                                 322       100             0.02                                                323       100             0.014                                               324       100             0.22                                                325       90              1.54                                                326       99              0.03                                                327       99              0.05                                                328       99              054                                                 329       84              ND                                                  330       92              0.85                                                331       99              0.06                                                332       100             0.07                                                333       100             0.15                                                334       99              0.05                                                335       89              ND                                                  336       100             0.04                                                337       99              0.29                                                338       99              0.93                                                339       99              0.012                                               340       56              ND                                                  341       99              2.1                                                 342       99              0.07                                                343       99              0.05                                                344       99              0.03                                                345       99              0.33                                                346       98              >50                                                 347       99              0.05                                                348       99              ND                                                  349       98              0.37                                                350       98              0.5                                                 351       99              0.08                                                352       99              0.1                                                 353       98              1.1                                                 354       99              0.12                                                355       99              0.07                                                356       99              0.12                                                357       99              0.11                                                358       99              0.1                                                 359       99              0.56                                                360       96              0.45                                                361       97              ND                                                  362       98              ND                                                  363       99              0.04                                                364       98              0.22                                                365       72              ND                                                  366       99              0.009                                               367       50              ND                                                  368       98              0.017                                               369       96              ND                                                  370       96              ND                                                  371       98              ND                                                  372       98              ND                                                  373       85              ND                                                  374       28              ND                                                  375       98              ND                                                  376       63              ND                                                  377       95              ND                                                  378       27              ND                                                  379       98              ND                                                  380       97              ND                                                  381       60              ND                                                  382       89              ND                                                  383       99              ND                                                  384       99              ND                                                  385       99              ND                                                  ______________________________________                                         ND = Not Determined                                                      

What we claim is:
 1. A compound of the following formula I: ##STR888##where A^(a) and A^(b) are independently:(1) hydrogen; (2) alkyl;##STR889## each E is independently a single bond or a peptide chaincontaining 1 to 4 amino acids, the N-terminus of which is bonded toA^(a) or A^(b) ; R³ and R⁴ are each independently:(1) hydrogen; (2)alkyl; (3) aryl; or (4) carbocyclo; R⁵, R⁶ and R⁷ are eachindependently:(1) hydrogen; (2) alkyl; (3) aryl; (4) carbocyclo; (5)fluorenyl; (6) R⁵, R⁶ and R⁷ may, independently, be joined together withthe carbon atom to which they are bonded, to form a mono-, bi- ortricyclic carbocyclic ring system; (7) alkynyl; or (8) alkenyl; each R⁸is independently:(1) hydrogen; or (2) alkyl; each R⁹ is independentlyarylalkyl; and Z is oxygen or sulfur; or a salt thereof,wherein:wherever they appear alone or as part of another group, unless otherwiseindicated, the terms "alk" or "alkyl" denote a straight or branchedchain saturated radical containing 1 to 12 carbons in the normal chain,optionally substituted by one or more groups selected from: (1) hydroxyor protected hydroxy; (2) oxo, with the proviso that the carbon bearingthe oxo group is not adjacent to a heteroatom; (3) carboxy, (4) halo;(5) alkoxy; (6) aryloxy; (7) alkoxycarbonyl; (8) (R¹²)(R¹³)N--C(O)--;(9) (R¹²)(R¹³)N--; (10) (R¹⁵)--C(O)--N(R¹⁴)--; (11) (R¹⁵)--SO₂--N(R¹⁴)--; (12) carbocyclo; (13) aryl; (14) alkylcarbonyloxy; (15)arylcarbonyloxy, (16) cyano; (17) mercapto; (18) alkenyl; (19) alkynyl;(20) alkylthio; (21) arylthio; (22) trialkylsilyl; (23) azo; or (24)(R¹²)(R¹³)N--C(O)--O--; wherever it appears alone or as part of anothergroup, unless otherwise indicated, the term "alkenyl" denotes a straightor branched chain radical containing 2 to 12 carbons in the normal chainwhich contains at least one carbon to carbon double bond and which isdirectly attached through one of the carbons composing said double bond,optionally substituted by one or more groups selected from: (1) alkyl;(2) aryl; (3) carbocyclo; (4) carboxy; (5) halo; (6)(R¹²)(R¹³)N--C(O)--; (7) cyano; (8) alkoxycarbonyl; (9) trialkylsilyl;or (10) alkynyl; wherever it appears alone or as part of another group,unless otherwise indicated, the term "alkynyl" denotes a straight orbranched chain radical containing 2 to 12 carbons in the normal chainwhich contains at least one carbon to carbon triple bond and which isdirectly attached through one of the carbons composing said triple bond,optionally substituted by one or more groups selected from: (1) alkyl;(2) aryl; (3) carbocyclo; (4) carboxy; (5) (R¹²)(R¹³)N--C(O)--; (6)cyano; (7) alkoxycarbonyl; (8) alkenyl; or (9) trialkylsilyl; whereverthey appear alone or as part of another group, unless otherwiseindicated, the terms "carbocyclo", "carbocyclic" or "carbocyclic ringsystem" denote a saturated or partially unsaturated, homocyclic carbonring system containing from 1 to 3 rings and from 3 to 12 carbons perhomocyclic ring, optionally substituted by one or more groups selectedfrom: (1) alkyl; (2) hydroxy or protected hydroxy, (3) halo; (4)mercapto; (5) cyano; (6) carboxy; (7) alkoxycarbonyl; (8)(R¹²)(R¹³)N--C(O)--; (9) alkylcarbonyloxy; (10) arylcarbonyloxy; (11)(R¹²)(R¹³)N--; (12) alkoxy; (13) aryl, where said aryl group may bebonded through a single bond or fused; (14) oxo; (15) aryloxy; (16)alkylthio; (17) arylthio; (18) (R¹⁵)--(O)--N(R¹⁴)--; (19) alkenyl; (20)alkynyl; or (21) trialkylsilyl; wherever it appears alone or as part ofanother group, unless otherwise indicated, the term "aryl" denotes, ahomocyclic, aromatic group containing 1 or 2 rings and from 6 to 12carbons in the aromatic ring portion, optionally substituted by one ormore groups selected from: (1) alkyl; (2) alkoxy; (3) hydroxy orprotected hydroxy; (4) halo; (5) (R¹²)(¹³)N--; (6) alkylthio; (7)mercapto; (8) nitro; (9) cyano; (10) carboxy; (11) carboalkoxy; (12)carbocyclo, where said carbocyclo group may be bonded through a singlebond or fused; (13) (R¹²)(R¹³)N--C(O)--; (14) (R¹²)(R¹³)N--SO₂ --; (15)R³ --C(O)--N(R¹⁷)--; (16) R³ --SO₂ --N(R¹⁷)--; (17) phenyl; (18)alkylcarbonyloxy; (19) arylcarbonyloxy; (20) arylthio; (21) aryloxy;(22) alkylthio; or (23) alkenyl; where R¹² and R¹³ are independently:(1)hydrogen; (2) alkyl; (3) aryl; or (4) carbocyclo; R¹⁴ is:(1) hydrogen;(2) alkyl; (3) aryl; or (4) carbocyclo; R¹⁵ is:(1) hydrogen; (2) alkyl;(3) alkenyl; (4) aryl; (5) carbocyclo; or ##STR890## wherein R⁵, R⁶ andR⁷ are, independently, those groups (1) through (8) recited for R⁵, R⁶and R⁷ above; and R¹⁷ is:(1) hydrogen; (2) alkyl; (3) aryl; or (4)carbocyclo.
 2. A compound of claim 1, wherein each R⁹ is independentlyaryl-C₁₋₆ alkyl which has the structure of the following formula:##STR891## where Ar(sub) is: (i) hydrogen;(ii) hydroxy; (iii) alkenyl;(iv) unsubstituted C₁₋₆ alkyl; or (v) alkoxy.
 3. A compound of claim 2,wherein Ar(sub) in each R⁹ is independently hydrogen; hydroxy; or C₁₋₆alkoxy, wherein said C₁₋₆ alkoxy is selected from the group consistingof: unsubstituted C₁₋₆ alkoxy; alkoxy-C₁₋₆ alkoxy; hydroxy-C₁₋₆ alkoxy;aryl-C₁₋₆ alkoxy; amino-C₁₋₆ alkoxy or aminocarbonyloxy-C₁₋₆ alkoxywhere the amino moiety is unsubstituted or mono- or disubstituted byalkyl or aryl; alkoxycarbonyl-C₁₋₆ alkoxy; and carboxy-C₁₋₆ alkoxy.
 4. Acompound of claim 1, wherein each R⁸ is hydrogen.
 5. A compound of claim3, wherein each R⁸ is hydrogen.
 6. A compound of claim 1, wherein each Eis independently a single bond or a peptide chain containing 1 or 2amino acids.
 7. A compound of claim 6, wherein each E is independently asingle bond; or a peptide chain containing 1 or 2 amino acids, whereinsaid amino acids independently have a structure of the followingformula: ##STR892## where R¹⁸ is hydrogen or unsubstituted C₁₋₆alkyl;R¹⁹ is hydrogen, aryl or C₁₋₆ alkyl; or R¹⁸ and R¹⁹, together withthe carbon atom to which they are bonded, form a cycloalkyl group; andR²⁰ is hydrogen or unsubstituted C₁₋₆ alkyl.
 8. A compound of claim 5,wherein each E is independently a single bond; or a peptide chaincontaining 1 or 2 amino acids, wherein said amino acids independentlyhave a structure of the following formula: ##STR893## where R¹⁸ ishydrogen or unsubstituted C₁₋₆ alkyl;R¹⁹ is hydrogen, aryl or C₁₋₆alkyl; or R¹⁸ and R¹⁹, together with the carbon atom to which they arebonded, form a cycloalkyl group; and R²⁰ is hydrogen or unsubstitutedC₁₋₆ alkyl.
 9. A compound of claim 1, wherein A^(a) and A^(b) areindependently:(A) hydrogen; (B) alkyl; (C) the group: ##STR894## whereR³ is alkyl;R⁴ is hydrogen or alkyl; and Z is oxygen or sulfur; (D) thegroup: ##STR895## where R⁵ is hydrogen; carbocyclo; alkyl; aryl; oralkynyl;R⁶ and R⁷ are hydrogen or alkyl; or two of R⁵, R⁶ and R⁷,together with the carbon atom to which they are bonded, form acarbocyclo group; (E) the group: ##STR896## where R³ is hydrogen; alkyl;aryl; or carbocyclo; andZ is oxygen or sulfur; or (F) the groups:

    R.sup.3 --SO.sub.2 --

    or

    R.sup.3 --SO--

where R³ is alkyl.
 10. A compound of claim 9, wherein A^(a) and A^(b)are independently:(C) the group: ##STR897## where R³ is unsubstitutedC₁₋₆ alkyl, or arylalkyl;R⁴ is hydrogen; and Z is oxygen; (D) the group:##STR898## where R⁵ is hydrogen, alkyl, or aryl;R⁶ and R⁷ are hydrogen,unsubstituted C₁₋₆ alkyl or hydroxyalkyl; or two of R⁵, R⁶ and R⁷,together with the carbon atom to which they are bonded, form acarbocyclo group; or (E) the group: ##STR899## where Z is oxygen; andR³is hydrogen; alkyl, wherein said alkyl is substituted by one or more ofhydroxy, aryl, alkylaminocarbonyl or fluoro; or carbocyclo, wherein saidcarbocyclo is substituted by one or more of alkyl, hydroxy, aryl,alkylaminocarbonyl or fluoro.
 11. A compound of claim 10, wherein A^(a)and A^(b) are independently:(D) the group ##STR900## where R⁵ ishydrogen, unsubstituted C₁₋₆ alkyl or phenyl; andR⁶ and R⁷ are hydrogen,unsubstituted C₁₋₆ alkyl or hydroxyalkyl; or (E) the group ##STR901##where Z is oxygen; andR³ is hydrogen; C₁₋₆ alkyl substituted with one ormore groups selected from the group consisting of hydroxy, fluoro andphenyl groups; or cycloalkyl substituted with one or more groupsselected from the group consisting of hydroxy and unsubstituted C₁₋₆alkyl groups.
 12. A compound of claim 8, wherein A^(a) and A^(b) areindependently:(D) the group ##STR902## where R⁵ is hydrogen,unsubstituted C₁₋₆ alkyl or phenyl; andR⁶ and R⁷ are hydrogen,unsubstituted C₁₋₆ alkyl or hydroxyalkyl; or (E) the group ##STR903##where Z is oxygen; andR³ is hydrogen; C₁₋₆ alkyl substituted with one ormore groups selected from the group consisting of hydroxy, fluoro andphenyl groups; or cycloalkyl substituted with one or more groupsselected from the group consisting of hydroxy and unsubstituted C₁₋₆alkyl groups.
 13. A compound of claim 1, which compound is selected fromthe group consistingof:[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethylester;[1S-[1R*,2S*(2S*,3R*)]]-3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(4-hydroxyphenyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid,1,1-dimethylethyl ester;[1R*,2S*(2S*,3R*)]-N-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-[(phenylmethoxy)carbonyl]-L-phenyl-alaninamide;[R-(R*,S*)]-[iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbamicacid, 1,1-dimethylethyl-2-hydroxy-1,1-dimethylethyl ester;[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxy-4-[4-(2-hydroxyethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester; [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-[4-(2-methoxyethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester; [1S-[1R*,2S*(2S*,3R*),(R*)]]-[3-[[3-[[3,3-dimethyl-2-(formylamino)-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester;[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-methoxycarbonyl)-3-methyl-L-valinamide;[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-hydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester;[1S-[1R*,2S*(2S*,3R*)]]-[2-hydroxy-1-(phenylmethyl)-3-[[2-hydroxy-4-phenyl-3-[(3,3,3-trifluoro-2-hydroxy-1-oxopropyl)amino]butyl]amino]propyl]carbamicacid, 1,1-dimethylethyl ester (isomer A);[1S-[1R*,2S*(2S*,3R*)]]-[2-hydroxy-3-[2-hydroxy-1-oxo-2-(trifluoromethyl)propyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethylester (isomer A);[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-(hydroxymethyl)-2-methylpropyl]carbamicacid, phenylmethyl ester, isomer A;[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2,2-dimethyl-1-hydroxycyclopentyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer B;[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-hydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 2-hydroxy-1,1-dimethylethyl ester;[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-hydroxy-3,3-dimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester;N,N'-[iminobis[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis-[1-hydroxy-2,2-dimethylcyclopentanecarboxamide],isomer A;[2R-[R*(R*,S*)]]-N,N'-[iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[2-hydroxy-2,3,3-trimethylbutaneamide];[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-hydroxy-1-oxo-2-phenylpropyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester;[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(2,4-dihydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxyl-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A;[1R*,2S*(2S*,3R*)]-N-[2-hydroxy-3-[[2-hydroxy-3-[[(2-hydroxy-1,1-dimethylethoxy)carbonyl]amino]-4-phenylbutyl]amino],1-(phenylmethyl)propyl]-N² -(2-methoxycarbonyl)-3-methyl-L-valinamide;[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-hydroxy-2-(hydroxymethyl)-3,3-dimethyl-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxyl-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A;[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,2-dimethyl-1-hydroxycyclopentyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 2-hydroxy-1,1-dimethylethyl ester, isomer A;[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[2-hydroxy-1-oxo-2-phenylethyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester;[1R*,2S*[2S*,3R*(S*)]]-N-[2-hydroxy-3-[[2-hydroxy-3-[(-2-hydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]-N.sup.2-(2-methoxycarbonyl)-3-methyl-L-valinamide;and stereoisomers andpharmaceutically acceptable salts thereof.
 14. A compound of claim 13,wherein said compound is selected from the group consistingof:[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester;[R-(R*,S*)]-[iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbamicacid, 1,1-dimethylethyl-2-hydroxy-1,1-dimethylethyl ester;[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N²-(2-methoxycarbonyl)-3-methyl-L-valinamide;[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-hydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxyl-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester;[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-hydroxy-3,3-dimethyl-1-oxobutyl)amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester;N,N'-[iminobis[(1S,2R)-2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis-[1-hydroxy-2,2-dimethylcyclopentanecarboxamide],isomer A; [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-hydroxy-2-(hydroxymethyl)-3,3-dimethyl-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 1,1-dimethylethyl ester, isomer A;[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,2-dimethyl-1-hydroxycyclopentyl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamicacid, 2-hydroxy-1,1-dimethylethyl ester, isomer A;and pharmaceuticallyacceptable salts thereof.
 15. A pharmaceutical composition for theinhibition of HIV protease, comprising a compound of claim 1 in amounteffective therefor, and a pharmaceutically acceptable vehicle ordiluent.
 16. A compound of claim 1, wherein said compound is in the formof a pharmaceutically acceptable acid addition salt selected from thegroup consisting of acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoatesalts.
 17. A compound which is capable of inhibiting HIV protease,wherein said compound contains the moiety: ##STR904## where each E isindependently a single bond or a peptide chain containing 1 to 4 aminoacids, the C-terminus of which is bonded to --N(R⁸)--;each R⁸ isindependently:(1) hydrogen; or (2) alkyl; and each R⁹ is independentlyarylalkyl;wherein: wherever they appear alone or as part of anothergroup, unless otherwise indicated, the terms "alk" or "alkyl" denote astraight or branched chain saturated radical containing 1 to 12 carbonsin the normal chain, optionally substituted by one or more groupsselected from: (1) hydroxy or protected hydroxy; (2) oxo, with theproviso that the carbon bearing the oxo group is not adjacent to aheteroatom; (3) carboxy; (4) halo; (5) alkoxy; (6) aryloxy; (7)alkoxycarbonyl; (8) (R¹²)(R¹³)N--C(O)--; (9) (R¹²)(R¹³)N--; (10)(R¹⁵)--C(O)--N(R¹⁴)--; (11) (R¹⁵)--SO₂ --N(R¹⁴)--; (12) carbocyclo; (13)aryl; (14) alkylcarbonyloxy; (15) arylcarbonyloxy; (16) cyano; (17)mercapto; (18) alkenyl; (19) alkynyl; (20) alkylthio; (21) arylthio;(22) trialkylsilyl; (23) azo; or (24) (R¹²)(R¹³)N--C(O)--O--; whereverit appears alone or as part of another group, unless otherwiseindicated, the term "alkenyl" denotes a straight or branched chainradical containing 2 to 12 carbons in the normal chain which contains atleast one carbon to carbon double bond and which is directly attachedthrough one of the carbons composing said double bond, optionallysubstituted by one or more groups selected from: (1) alkyl; (2) aryl;(3) carbocyclo; (4) carboxy; (5) halo; (6) (R¹²)(R¹³)N--C(O)--; (7)cyano; (8) alkoxycarbonyl; (9) trialkylsilyl; or (10) alkynyl; whereverit appears alone or as part of another group, unless otherwiseindicated, the term "alkynyl" denotes a straight or branched chainradical containing 2 to 12 carbons in the normal chain which contains atleast one carbon to carbon triple bond and which is directly attachedthrough one of the carbons composing said triple bond, optionallysubstituted by one or more groups selected from: (1) alkyl; (2) aryl;(3) carbocyclo; (4) carboxy; (5) (R¹²)(R¹³)N--C(O)--; (6) cyano; (7)alkoxycarbonyl; (8) alkenyl; or (9) trialkylsilyl; wherever they appearalone or as part of another group, unless otherwise indicated, the terms"carbocyclo", "carbocyclic" or "carbocyclic ring system" denote asaturated or partially unsaturated, homocyclic carbon ring systemcontaining from 1 to 3 rings and from 3 to 12 carbons per homocyclicring, optionally substituted by one or more groups selected from: (1)alkyl; (2) hydroxy or protected hydroxy; (3) halo; (4) mercapto; (5)cyano; (6) carboxy; (7) alkoxycarbonyl; (8) (R¹²)(R¹³)N--C(O)--; (9)alkylcarbonyloxy; (10) arylcarbonyloxy; (11) (R¹²)(R¹³)N--; (12) alkoxy;(13) aryl, where said aryl group may be bonded through a single bond orfused; (14) oxo; (15) aryloxy; (16) alkylthio; (17) arylthio; (18)(R¹⁵)-C(O)--N(R¹⁴)--; (19) alkenyl; (20) alkynyl; or (21) trialkylsilyl;wherever it appears alone or as part of another group, unless otherwiseindicated, the term "aryl" denotes a homocyclic, aromatic groupcontaining 1 or 2 rings and from 6 to 12 carbons in the aromatic ringportion, optionally substituted by one or more groups selected from: (1)alkyl; (2) alkoxy; (3) hydroxy or protected hydroxy; (4) halo; (5)(R¹²)(13)N--; (6) alkylthio; (7) mercapto; (8) nitro; (9) cyano; (10)carboxy; (11) carboalkoxy; (12) carbocyclo, where said carbocyclo groupmay be bonded through a single bond or fused; (13) (R¹²)(R¹³)N--C(O)--;(14) (R¹²)(R¹³)N--SO₂ --; (15) R³ --C(O)--N(R¹⁷)--; (16) R³ --SO₂--N(R¹⁷)--; (17) phenyl; (18) alkylcarbonyloxy; (19) arylcarbonyloxy;(20) arylthio; (21) aryloxy; (22) alkylthio; or (23) alkenyl; where R¹²and R¹³ are independently:(1) hydrogen; (2) alkyl; (3) aryl; or (4)carbocyclo; R¹⁴ is:(1) hydrogen; (2) alkyl; (3) aryl; or (4) carbocyclo;R¹⁵ is:(1) hydrogen; (2) alkyl; (3) alkenyl; (4) aryl; (5) carbocyclo;or ##STR905## wherein R⁵, R⁶ and R⁷ are, independently, those groups (1)through (8) recited for R⁵, R⁶ and R⁷ below; R¹⁷ is:(1) hydrogen; (2)alkyl; (3) aryl; or (4) carbocyclo; R³ is:(1) hydrogen; (2) alkyl; (3)aryl; or (4) carbocyclo; R⁵, R⁶ and R⁷ are each independently:(1)hydrogen; (2) alkyl; (3) aryl; (4) carbocyclo; (5) fluorenyl; (6) R⁵, R⁶and R⁷ may, independently, be joined, together with the carbon atom towhich they are bonded, to form a mono-, bi- or tricyclic carbocyclicring system; (7) alkynyl; or (8) alkenyl;or a salt thereof.
 18. Acompound of the following formula I: ##STR906## where A^(a) and A^(b)are independently:(1) hydrogen; (2) alkyl; ##STR907## each E isindependently a single bond or a peptide chain containing 1 to 4 aminoacids, the N-terminus of which is bonded to A^(a) or A^(b) ; R³ and R⁴are each independently:(1) hydrogen; (2) alkyl; (3) aryl; or (4)carbocyclo; R⁵, R⁶ and R⁷ are each independently:(1) hydrogen; (2)alkyl; (3) aryl; (4) carbocyclo; (5) fluorenyl; (6) R⁵, R⁶ and R⁷ may,independently, be joined, together with the carbon atom to which theyare bonded, to form a mono-, bi- or tricyclic carbocyclic ring system;(7) alkynyl; or (8) alkenyl; each R⁸ is independently:(1) hydrogen; or(2) alkyl; each R⁹ is independently arylalkyl; and Z is oxygen orsulfur; or a salt thereof,wherein: wherever they appear alone or as partof another group, unless otherwise indicated, the terms "alk" or "alkyl"denote a straight or branched chain saturated radical containing 1 to 12carbons in the normal chain, optionally substituted by one or moregroups selected from: (1) hydroxy; (2) oxo, with the proviso that thecarbon bearing the oxo group is not adjacent to a heteroatom; (3)carboxy; (4) halo; (5) alkoxy; (6) aryloxy; (7) alkoxycarbonyl; (8)(R¹²)(R¹³)N--C(O)--; (9) (R¹²)(R¹³)N--; (10) (R¹⁵)--C(O)--N(R¹⁴)--; (11)(R¹⁵)--SO₂ --N(R¹⁴)--; (12) carbocyclo; (13) aryl; (14)alkylcarbonyloxy; (15) arylcarbonyloxy; (16) cyano; (17) mercapto; (18)alkenyl; (19) alkynyl; (20) alkylthio; (21) arylthio; or (22)trialkylsilyl; wherever it appears alone or as part of another group,unless otherwise indicated, the term "alkenyl" denotes a straight orbranched chain radical containing 2 to 12 carbons in the normal chainwhich contains at least one carbon to carbon double bond and which isdirectly attached through one of the carbons composing said double bond,optionally substituted by one or more groups selected from: (1) alkyl;(2) aryl; (3) carbocyclo; (4) carboxy; (5) halo; (6)(R¹²)(R¹³)N--C(O)--; (7) cyano; (8) alkoxycarbonyl; (9) trialkylsilyl;or (10) alkynyl; wherever it appears alone or as part of another group,unless otherwise indicated, the term "alkynyl" denotes a straight orbranched chain radical containing 2 to 12 carbons in the normal chainwhich contains at least one carbon to carbon triple bond and which isdirectly attached through one of the carbons composing said triple bond,optionally substituted by one or more groups selected from: (1) alkyl;(2) aryl; (3) carbocyclo; (4) carboxy; (5) (R¹²)(R¹³)N--C(O)--; (6)cyano; (7) alkoxycarbonyl; (8)alkenyl; or (9) trialkylsilyl; whereverthey appear alone or as part of another group, unless otherwiseindicated, the terms "carbocyclo", "carbocyclic" or "carbocyclic ringsystem" denote a saturated or partially unsaturated, homocyclic carbonring system containing from 1 to 3 rings and from 3 to 12 carbons perhomocyclic ring, optionally substituted by one or more groups selectedfrom: (1) alkyl; (2) hydroxy; (3) halo; (4) mercapto; (5) cyano; (6)carboxy; (7) alkoxycarbonyl; (8) (R¹²)(R¹³)N--C(O)--; (9)alkylcarbonyloxy; (10) arylcarbonyloxy; (11) (R¹²)(R¹³)N--; (12) alkoxy;(13) aryl, where said aryl group may be bonded through a single bond orfused; (14) oxo; (15) aryloxy; (16) alkylthio; (17) arylthio; (18)(R¹⁵)--C(O)--N(R¹⁴)--; (19) alkenyl; (20) alkynyl; or (21)trialkylsilyl; wherever it appears alone or as part of another group,unless otherwise indicated, the term "aryl" denotes a homocyclic,aromatic group containing 1 or 2 rings and from 6 to 12 carbons in thearomatic ring portion, optionally substituted by one or more groupsselected from: (1) alkyl; (2) alkoxy; (3) hydroxy; (4) halo; (5)(R¹²)(¹³)N--; (6) alkylthio; (7) mercapto; (8) nitro; (9) cyano; (10)carboxy; (11) carboalkoxy; (12) carbocyclo, where said carbocyclo groupmay be bonded through a single bond or fused; (13) (R¹²)(R¹³)N--C(O)--;(14) (R¹²)(R¹³)N--SO₂ --; (15) R³ --C(O--N(R¹⁷)--; (16) R³ --SO₂--N(R¹⁷)--; (17) phenyl; (18) alkylcarbonyloxy; (19) arylcarbonyloxy;(20) arylthio; (21) aryloxy; or (22) alkylthio; where R¹² and R¹³ areindependently:(1) hydrogen; (2) alkyl; (3)aryl; or (4) carbocyclo; R¹⁴is:(1) hydrogen; (2) alkyl; (3) aryl; or (4) carbocyclo; R¹⁵ is:(1)hydrogen; (2) alkyl; (3) alkenyl; (4) aryl; (5) carbocyclo; or##STR908## wherein R⁵, R⁶ and R⁷ are, independently, those groups (1)through (8) recited for R⁵, R⁶ and R⁷ above; and R¹⁷ is:(1) hydrogen;(2) alkyl; (3) aryl; or (4) carbocyclo.